Hiv protease inhibitors, compositions containing the same, their pharmaceutical uses, materials for their synthesis

ABSTRACT

Compounds of the formula:  
                 
where the formula variables are as defined herein, are disclosed that advantageously inhibit or block the biological activity of the HIV protease. These compounds, as well as pharmaceutical compositions containing these compounds, are useful for treating patients or hosts infected with the HIV virus. Intermediates and synthetic methods for preparing such compounds are also described.

This application is a continuation of U.S. application Ser. No.10/728,602, filed Dec. 4, 2003, which application is acontinuation-in-part of U.S. application Ser. No. 10/166,957, filed Jun.11, 2002, which claims the benefit of U.S. Provisional Application No.60/297,460, filed on Jun. 11, 2001, and U.S. Provisional Application No.60/297,729, filed on Jun. 11, 2001, all of which are hereby incorporatedby reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel compounds as useful as HIV proteaseinhibitors and to the use of such compounds as antiviral agents fortreatment of HIV infected individuals. This invention also relates tomethods of preparation of these compounds and to intermediates that areuseful in the preparation thereof.

2. Related Background Art

Acquired Immune Deficiency Syndrome (AIDS) causes a gradual breakdown ofthe body's immune system as well as progressive deterioration of thecentral and peripheral nervous systems. Since its initial recognition inthe early 1980's, AIDS has spread rapidly and has now reached epidemicproportions within a relatively limited segment of the population.Intensive research has led to the discovery of the responsible agent,human T-lymphotropic retrovirus III (HTLV-III), now more commonlyreferred to as the human immunodeficiency virus or HIV.

HIV is a member of the class of viruses known as retroviruses. Theretroviral genome is composed of RNA, which is converted to DNA byreverse transcription. This retroviral DNA is then stably integratedinto a host cell's chromosome and, employing the replicative processesof the host cells, produces new retroviral particles and advances theinfection to other cells. HIV appears to have a particular affinity forthe human T-4 lymphocyte cell, which plays a vital role in the body'simmune system. HIV infection of these white blood cells depletes thiswhite cell population. Eventually, the immune system is renderedinoperative and ineffective against various opportunistic diseases suchas, among others, pneumocystic carini pneumonia, Kaposi's sarcoma, andcancer of the lymph system.

Although the exact mechanism of the formation and working of the HIVvirus is not understood, identification of the virus has led to someprogress in controlling the disease. For example, the drugazidothymidine (AZT) has been found effective for inhibiting the reversetranscription of the retroviral genome of the HIV virus, thus giving ameasure of control, though not a cure, for patients afflicted with AIDS.The search continues for drugs that can cure or at least provide animproved measure of control of the deadly HIV virus.

Retroviral replication routinely features post-translational processingof polyproteins. This processing is accomplished by virally encoded HIVprotease enzyme. This yields mature polypeptides that will subsequentlyaid in the formation and function of infectious virus. If this molecularprocessing is stifled, then the normal production of HIV is terminated.Therefore, inhibitors of HIV protease may function as anti-HIV viralagents.

HIV protease is one of the translated products from the HIV structuralprotein pol gene. This retroviral protease specifically cleaves otherstructural polypeptides at discrete sites to release these newlyactivated structural proteins and enzymes, thereby rendering the virionreplication-competent. As such, inhibition of the HIV protease by potentcompounds may prevent proviral integration of infected T-lymphocytesduring the early phase of the HIV-1 life cycle, as well as inhibit viralproteolytic processing during its late stage. Additionally, the proteaseinhibitors may have the advantages of being more readily available,longer lived in virus, and less toxic than currently available drugs,possibly due to their specificity for the retroviral protease.

Related inhibitors of HIV proteases have been described in, e.g., U.S.Pat. No. 5,962,640, U.S. Pat. No. 5,932,550, Australian Patent No.705193, Canadian Patent Application No. 2,179,935, European PatentApplication No. 0 751 145, and Japanese Patent Application No.100867489.Other related HIV protease inhibitors have been described in K.Yoshimura, et al., Proct. Natl. Acad. Sci. USA, 96, 8675-8680 (1999) andT. Mimoto, et al., J. Med. Chem., 42, 1789-1802 (1999).

On-going treatment of HIV-infected individuals with compounds thatinhibit HIV protease has led to the development of mutant viruses thatpossess proteases that are resistant to the inhibitory effect of thesecompounds. Thus, to be effective, new HIV protease inhibitors must beeffective not only against wild-type strains of HIV, but must alsodemonstrate efficacy against the newly emerging mutant strains that areresistant to the commercially available protease inhibitors.Accordingly, there continues to be a need for new inhibitors targetingthe HIV protease in both wild type and mutant strains of HIV.

SUMMARY OF THE INVENTION

This invention relates to compounds useful for inhibiting the activityof HIV-protease of Formula I:

wherein:

R¹ is a 5- or 6-membered mono-cyclic carbocyclic or heterocyclic group,wherein said carbocyclic or heterocyclic group is saturated, partiallyunsaturated or fully unsaturated and is unsubstituted or substituted byone or more suitable substituents;

R² is a substituted alkyl group, a substituted or unsubstituted alkenylgroup, a substituted or unsubstituted alkynyl group, a substitutedphenyl group, a substituted phenylalkyl group, a substituted orunsubstituted phenylalkenyl group or a substituted or unsubstitutedphenylalkynyl group,

R^(2′) is H or a substituted or unsubstituted C₁-C₄ alkyl group;

X is

wherein R^(x) is H or one or more suitable substituents;

Z is S, O, SO, SO₂, CH₂ or CFH;

R³ is H or an optionally substituted or unsubstituted C₁-C₄ alkyl group;

R⁴, R⁵, R⁶ and R⁷ are independently selected from H or C₁-C₆ alkylgroup; and

R⁸ and R^(8′) are independently selected from H, halo, a C₁-C₄ aliphaticgroup or a C₁-C₄ halo-substituted aliphatic group;

where any of said substituted alkyl, alkenyl or alkynyl groups aresubstituted by one or more suitable substituents provided that said 5-or 6-membered mono-cyclic heterocycloalkyl, heterocycloalkenyl orheteroaryl group contains at least two heteroatoms when R² is asubstituted phenyl group, a substituted phenylalkyl group, a substitutedor unsubstituted phenylalkenyl group or a substituted or unsubstitutedphenylalkynyl group; or

provided that said alkyl, alkenyl or alkynyl moiety of said substitutedphenylalkyl, phenylalkenyl or phenylalkynyl group is substituted by oneor more substituents selected from halo or keto; or

provided that said substituted phenyl group or phenyl moiety of saidsubstituted phenylalkyl, phenylalkenyl or phenylalkynyl group issubstituted by one or more suitable substituents other than halo ormethyl.

The present invention relates to compounds of Formula I below, andprodrugs, pharmaceutically active metabolites, and pharmaceuticallyacceptable salts and solvates thereof that inhibit the protease encodedby human immunodeficiency virus (HIV) type 1 (HIV-1) or type 2 (HIV-2),as well as mutant strains thereof. These compounds are useful in thetreatment of infection by HIV and the treatment of the acquired immunedeficiency syndrome (AIDS). The compounds, their pharmaceuticallyacceptable salts, and the pharmaceutical compositions of the presentinvention can be used alone or in combination with other antivirals,immunomodulators, antibiotics or vaccines. Compounds of the presentinvention can also be converted to prodrugs, by derivatization,according to conventional techniques. Methods of treating AIDS, methodsof treating HIV infection and methods of inhibiting HIV protease aredisclosed.

The present invention also relates to methods and processes useful forthe preparation of compounds of formula I.

Furthermore, the present invention relates to chemical intermediatesthat are useful in the preparation of compounds of formula I.

DETAILED DESCRIPTION OF INVENTION AND PREFERRED EMBODIMENTS

The term “reacting,” as used herein, refers to a chemical process orprocesses in which two or more reactants are allowed to come intocontact with each other to effect a chemical change or transformation.For example, when reactant A and reactant B are allowed to come intocontact with each other to afford a new chemical compound(s) C, A issaid to have “reacted” with B to produce C.

The term “protecting,” as used herein, refers to a process in which afunctional group in a chemical compound is selectively masked by anon-reactive functional group in order to allow a selective reaction(s)to occur elsewhere on said chemical compound. Such non-reactivefunctional groups are herein termed “protecting groups.” For example,the term “hydroxyl protecting group,” as used herein refers to thosegroups that are capable of selectively masking the reactivity of ahydroxyl (—OH) group. The term “suitable protecting group,” as usedherein refers to those protecting groups that are useful in thepreparation of the compounds of the present invention. Such groups aregenerally able to be selectively introduced and removed using mildreaction conditions that do not interfere with other portions of thesubject compounds. Protecting groups that are suitable for use in theprocesses and methods of the present invention are known to those ofordinary skill in the art. The chemical properties of such protectinggroups, methods for their introduction and their removal can be found,for example, in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999). The terms“deprotecting,” “deprotected,” or “deprotect,” as used herein, are meantto refer to the process of removing a protecting group from a compound.

The term “leaving group,” as used herein refers to a chemical functionalgroup that generally allows a nucleophilic substitution reaction to takeplace at the atom to which it is attached. For example, in acidchlorides of the formula Cl—C(O)R, wherein R is alkyl, aryl, orheterocyclic, the —Cl group is generally referred to as a leaving groupbecause it allows nucleophilic substitution reactions to take place atthe carbonyl carbon. Suitable leaving groups are known to those ofordinary skill in the art and can include halides, aromaticheterocycles, cyano, amino groups (generally under acidic conditions),ammonium groups, alkoxide groups, carbonate groups, formates, andhydroxy groups that have been activated by reaction with compounds suchas carbodiimides. For example, suitable leaving groups can include, butare not limited to, chloride, bromide, iodide, cyano, imidazole, andhydroxy groups that have been allowed to react with a carbodiimide suchas dicyclohexylcarbodiimide (optionally in the presence of an additivesuch as hydroxybenzotriazole) or a carbodiimide derivative.

The term “C₁₋₆ alkylcarbonyloxy,” as used herein, refers to groups ofthe formula —OC(O)R, wherein R is an alkyl group comprising from 1 to 6carbon atoms.

The term “C₆₋₁₀ arylcarbonyloxy,” as used herein, refers to a group ofthe formula —OC(O)R, wherein R is an aryl group comprising from 6 to 10carbons.

The term “heteroarylcarbonyloxy,” as used herein, refers to a group ofthe formula —OC(O)R, wherein R is a heteroaromatic group as definedabove.

In accordance with a convention used in the art,

is used in structural formulas herein to depict the bond that is thepoint of attachment of the moiety or substituent to the core or backbonestructure. When the phrase, “substituted with at least one substituent”is used herein, it is meant to indicate that the group in question maybe substituted by at least one of the substituents chosen. The number ofsubstituents a group in the compounds of the invention may have dependson the number of positions available for substitution. For example, anaryl ring in the compounds of the invention may contain from 1 to 5additional substituents, depending on the degree of substitution presenton the ring. The maximum number of substituents that a group in thecompounds of the invention may have can be determined by those ofordinary skill in the art.

As used herein, the term “aliphatic” represents a saturated orunsaturated, straight- or branched-chain hydrocarbon, containing 1 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. The term “aliphatic” is intended toencompass alkyl, alkenyl and alkynyl groups.

As used herein, the term “alkyl” represents a straight- orbranched-chain saturated or unsaturated hydrocarbon, containing 1 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkyl substituents include,but are not limited to methyl (Me), ethyl (Et), propyl, isopropyl,butyl, isobutyl, t-butyl, and the like. The term “lower alkyl” refers toan alkyl group containing from 1 to 6 carbon atoms

The term “alkenyl” represents a straight- or branched-chain hydrocarbon,containing one or more carbon-carbon double bonds and having 2 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary alkenyl substituentsinclude, but are not limited to ethenyl, propenyl, butenyl, allyl,pentenyl and the like.

The term “alkynyl” represents a straight- or branched-chain hydrocarbon,containing one or more carbon-carbon triple bonds and having 2 to 10carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. An alkynyl moiety may also contain oneor more carbon-carbon double bonds. Exemplary alkynyl substituentsinclude, but are not limited to ethynyl, butynyl, propynyl (propargyl)isopropynyl, pentynyl, hexynyl and the like.

The term “carbocyclic” represents a saturated, partially saturated, orfully unsaturated (aromatic) cyclic hydrocarbon group containing from 3to 14 carbon atoms which may be unsubstituted or substituted by one ormore of the substituents described herein below. The term “carbocyclic”is intended to encompass mono-, bi- and tri-cyclic saturated, partiallysaturated, or fully unsaturated hydrocarbon groups; for example,cycloalkyl, cycloalkenyl and aryl groups. The term “carbocyclic” is alsointended to encompass bi- and tri-cyclic hydrocarbon groups whichcontain any combination of ring moieties that are saturated, partiallysaturated, or fully unsaturated (aromatic). Partially saturatedcarbocycles include, for example, dihydroarenes (e.g., indanyl) ortetra-hydro-arenes (e.g. tetrahydronaphthalene), wherein any one or morepoints of saturation may occur in any ring moiety of the carbocycle. Inaddition, it is understood that bonding between any bi- or tri-cycliccarbocyclic group and any other substituent or variable group may bemade at any suitable position of the carbocycle. The term“carbocyclic-aliphatic” group is intended to encompass aliphatic groupshaving a carbocyclic substituent (e.g., phenylmethyl- (benzyl),phenylethyl-, cyclopropylmethyl-, etc.), wherein the carbocyclic moietyand the aliphatic moiety thereof may be independently substituted by oneor more suitable substituents.

The term “cycloalkyl” represents a group comprising a non-aromaticmonocyclic, bicyclic, or tricyclic hydrocarbon containing from 3 to 14carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below. Exemplary cycloalkyls includemonocyclic rings having from 3-8 carbon atoms, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Illustrative examples of cycloalkyl groups include the following:

The term “cycloalkenyl” represents a group comprising a non-aromaticmonocyclic, bicyclic, or tricyclic hydrocarbon containing from 4 to 14carbon atoms which may be unsubstituted or substituted by one or more ofthe substituents described below and contains at least one carbon-carbondouble bond. Exemplary monocyclic cycloalkenyls include groups havingfrom 4-8, preferably 5-6, carbon atoms, such as cyclopentenyl,cyclopentadienyl, cyclohexenyl, cycloheptenyl and the like. Illustrativeexamples of cycloalkenyl groups include the following:

The term “aryl” represents a group comprising an aromatic, monovalentmonocyclic, bicyclic, or tricyclic radical containing from 6 to 18carbon ring atoms, which may be unsubstituted or substituted by one ormore of the substituents described below.

The term “carbocyclic” also to encompasses mixed bi- and tri-cycliccycloalkyl/cycloalkenyl/aryl groups, which may be unsubstituted orsubstituted by one or more of the substituents described below.Illustrative examples of such mixed bi- and tri-cyclic groups includethe following:

It is understood that bonding or substitution of any bi-cyclic ortri-cyclic carbocyclic or heterocyclic group described herein may be atany suitable position on any ring.

Illustrative examples of such bonding in mixed bi-and tri-cycliccarbocyclic groups include the following:

wherein R′ is any suitable substituent.

The term “heterocyclic” represents a saturated, partially saturated, orfully unsaturated (aromatic) cyclic group containing from 3 to 18 ringatoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygenand sulfur, and which may be unsubstituted or substituted by one or moreof the substituents described herein below. The term “heterocyclic” isintended to encompass mono-, bi- and tri-cyclic saturated, partiallysaturated, or fully unsaturated heteroatom-containing cyclic groups; forexample, heterocycloalkyl, heterocycloalkenyl and heteroaryl groups. Theterm “heterocyclic” is also intended to encompass bi- and tri-cyclicgroups which contain any combination of ring moieties that aresaturated, partially saturated, or fully unsaturated (aromatic).Partially saturated heterocycles include, for example,dihydroheteroarenes (e.g., dihydroindole) or tetrahydro-heteroarenes(e.g. tetrahydroquinoline), wherein any one or more points of saturationmay occur in any ring moiety of the heterocycle. In addition, it isunderstood that bonding between any bi- or tri-cyclic heterocyclic groupand any other substituent or variable group may be made at any suitableposition of the heterocycle (i.e., there is no restriction that asubstituent or variable group must be bonded to theheteroatom-containing moiety of a bi- or tri-cyclic heterocyclic group).The term “heterocyclic-aliphatic” group is intended to encompassaliphatic groups having a heterocyclic substituent (e.g.,pyridylmethyl-, thiazolylmethyl-, tetrahydrofuranylmethyl-, etc.)wherein the heterocyclic moiety and the aliphatic moiety thereof may beindependently substituted by one or more suitable substituents.

“Heterocycloalkyl” represents a group comprising a saturated monovalentmonocyclic, bicyclic, or tricyclic radical, containing 3 to 18 ringatoms, which includes 1 to 5 heteroatoms selected from nitrogen, oxygenand sulfur, and which may be unsubstituted or substituted by one or moreof the substituents described below. Illustrative examples ofheterocycloalkyl groups include, but are not limited to, azetidinyl,pyrrolidyl, piperidyl, piperazinyl, morpholinyl,tetrahydro-2H-1,4-thiazinyl, tetrahydrofuryl, tetrahydropyranyl,1,3-dioxolanyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-oxathiolanyl,1,3-oxathianyl, 1,3-dithianyl, azabicylo[3.2.1]octyl,azabicylo[3.3.1]nonyl, azabicylo[4.3.0]nonyl, oxabicylo[2.2.1]heptyl,1,5,9-triazacyclododecyl, and the like. Illustrative examples ofheterocycloalkyl groups include the following:

wherein R is H, alkyl, hydroxyl or represents a compound according toFormula I, and the bond depicted as

represents bonding to either face of the bi-cyclic moiety (i.e., endo orexo).

The term “heterocycloalkenyl” is used herein to represent anon-aromatic, monovalent monocyclic, bicyclic, or tricyclic radical,containing 4 to 18 ring atoms, which may include from 1 to 5 heteroatomsselected from nitrogen, oxygen and sulfur, and which may beunsubstituted or substituted by one or more of the substituentsdescribed below and which contains at least one carbon-carbon orcarbon-heteroatom double bond. Exemplary monocyclic heterocycloalkenylsinclude groups having from 4-8, preferably 5-6, ring atoms. Illustrativeexamples of heterocycloalkenyl groups include, but are not

limited to, dihydrofuryl, dihydropyranyl, isoxazolinyl, dihydropyridyl,tetrahydropyridyl, and the like. Illustrative examples ofheterocycloalkenyl groupsinclude the following:

wherein R is H, alkyl, hydroxyl or represents a compound according toFormula I.

The term “Heteroaryl” represents a group comprising an aromaticmonovalent monocyclic, bicyclic, or tricyclic radical, containing 5 to18 ring atoms, including 1 to 5 heteroatoms selected from nitrogen,oxygen and sulfur, which may be unsubstituted or substituted by one ormore of the substituents described below. As used herein, the term“heteroaryl” is also intended to encompass the N-oxide derivative (orN-oxide derivatives, if the heteroaryl group contains more than onenitrogen such that more than one N-oxide derivative may be formed) ofthe nitrogen-containing heteroaryl groups described herein. Illustrativeexamples of heteroaryl groups include, but are not limited to, thienyl,pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl,isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,triazinyl, benzo[b]thienyl, naphtho[2,3-b]thianthrenyl, isobenzofuranyl,chromenyl, xanthenyl, phenoxathienyl, indolizinyl, isoindolyl, indolyl,indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxyalinyl, quinzolinyl, benzothiazolyl, benzimidazolyl,tetrahydroquinolinyl, cinnolinyl, pteridinyl, carbazolyl,beta-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, andphenoxazinyl. Illustrative examples of N-oxide derivatives of heteroarylgroups include, but are not limited to, pyridyl N-oxide, pyrazinylN-oxide, pyrimidinyl N-oxide, pyridazinyl N-oxide, triazinyl N-oxide,isoquinolyl N-oxide, and quinolyl N-oxide. Further examples ofheteroaryl groups include the following moieties:

wherein R is H, alkyl, hydroxyl or represents a compound according toFormula I.

The term “heterocyclic” also to encompasses mixed bi- and tri-cyclicheterocycloalkyl/heterocycloalkenyl/heteroaryl groups, which may beunsubstituted or substituted by one or more of the substituentsdescribed below. Illustrative examples of such mixed bi-and tri-cyclicheterocyclic groups include the following:

Illustrative examples of such bonding in mixed bi-and tri-cyclicheterocyclic groups include the following:

wherein R′ is any suitable substituent.

In the compounds of this invention, the alkyl, alkenyl and alkynylgroups may be optionally substituted by one or more suitablesubstituents independently selected from phenyl, nitro, amino, cyano,halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, cycloalkyloxy,cycloalkylalkyloxy, cycloalkenyloxy, cycloalkenylalkyloxy,heterocycloalkoxy, heterocycloalkylalkyloxy, heterocycloalkenyloxy,heterocycloalkenylalkyloxy, heteroaryloxy, alkylcarbonyl,alkenylcarbonyl, alkynylcarbonyl, alkyloxycarbonyl, alkenyloxycarbonyl,alkynyloxycarbonyl, alkylcarbonyloxy, alkenylcarbonyloxy,alkynylcarbonyloxy, arylcarbonyl, arylcarbonyloxy, aryloxycarbonyl,cycloalkylcarbonyl, cycloalkylcarbonyloxy, cycloalkyoxycarbonyl,heteroarylcarbonyl, heteroarylcarbonyloxy, heteroaryloxycarbonyl,heterocycloalkylcarbonyl, heterocycloalkylcarbonyloxy,heterocycloalkyoxycarbonyl, carboxyl, carbamoyl, formyl, keto (oxo),thioketo, sulfo, alkylamino, alkenylamino, alkynylamino,cycloalkylamino, cycloalkenylamino, arylamino, heterocycloalkylamino,heterocycloalkenylamino, heteroarylamino, dialkylamino,alkylaminocarbonyl, alkenylaminocarbonyl, alkynylaminocarbonyl,cycloalkylaminocarbonyl, cycloalkenylamino, arylaminocarbonyl,heterocycloalkylaminocarbonyl, heterocycloalkenylcarbonyl,heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio andheteroarylthio groups, wherein any of the alkyl, alkenyl, alkynyl, aryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl,heteroaryl moieties present in the above substituents may be furthersubstituted. The alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl moieties ofany of the above substituents may be optionally substituted by one ormore groups independently selected from alkyl (except for alkyl),haloalkyl, aryl, nitro, amino, alkylamino, dialkylamino, halogen,hydroxyl, alkoxy, haloalkoxy, aryloxy, mercapto, alkylthio,haloalkylthio or arylthio groups.

In the compounds of this invention the substituted carbocyclic orheterocyclic groups may be optionally substituted by one or moresuitable substituents independently selected from alkyl, haloalkyl,alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, nitro, amino, cyano, halogen, hydroxyl,alkoxy, haloalkoxy, alkenyloxy, alkynyloxy, alkylenedioxy, aryloxy,cycloalkyloxy, cycloalkylalkyloxy, cycloalkenyloxy,cycloalkenylalkyloxy, heterocycloalkoxy, heterocycloalkylalkyloxy,heterocycloalkenyloxy, heterocycloalkenylalkyloxy, heteroaryloxy,alkylcarbonyl, alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl,arylcarbonyloxy, aryloxycarbonyl, cycloalkylcarbonyl,cycloalkylcarbonyloxy, cycloalkyoxycarbonyl, heteroarylcarbonyl,heteroarylcarbonyloxy, heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino,cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino,dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl,arylaminocarbonyl, heterocycloalkylaminocarbonyl,heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio andheteroarylthio groups, wherein any of the alkyl, alkylene, aryl,cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the abovesubstituents may be further substituted. Preferred “suitablesubstituents” include alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, halogen, hydroxyl, alkoxy, alkylenedioxy,aryloxy, cycloalkoxy, heteroaryloxy, alkylthio, haloalkylthio andcarboxyl. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl moieties of any of the above substituents may be optionallysubstituted by one or more groups independently selected from: alkyl,haloalkyl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl,alkoxy, haloalkoxy, mercapto, alkylthio, haloalkylthio or arylthiogroups.

For example, in the compounds of this invention, the substituted phenylor phenyl moiety of R may comprise at least one substituent (other thanhalo or methyl) selected from haloalkyl, hydroxyalkyl, alkoxyalkyl,cycloalkoxyalkyl, alkylcarbonylalkyl, haloalkoxyalkyl, aryloxyalkyl,alkylthioalkyl, haloalkylthioalkyl, arylthioalkyl, cyanoalkyl,aminoalkyl, alkylaminoalkyl, alkenyl, alkynyl, aryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, heteroaryl, nitro,amino, cyano, hydroxyl, alkoxy, haloalkoxy, alkenyloxy, alkynyloxy,alkylenedioxy, aryloxy, cycloalkyloxy, cycloalkylalkyloxy,cycloalkenyloxy, cycloalkenylalkyloxy, heterocycloalkoxy,heterocycloalkylalkyloxy, heterocycloalkenyloxy,heterocycloalkenylalkyloxy, heteroaryloxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy,aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy,cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy,heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto (oxo), thioketo, sulfo, alkylamino,cycloalkylamino, arylamino, heterocycloalkylamino, heteroarylamino,dialkylamino, alkylaminocarbonyl, cycloalkylaminocarbonyl,arylaminocarbonyl, heterocycloalkylaminocarbonyl,heteroarylaminocarbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio andheteroarylthio groups, wherein any of the alkyl, alkylene, aryl,cycloalkyl, heterocycloalkyl, heteroaryl moieties present in the abovesubstituents may be further substituted. Preferred “suitablesubstituents” include alkyl, alkenyl, alkynyl, aryl, cycloalkyl,heterocycloalkyl, heteroaryl, halogen, hydroxyl, alkoxy, alkylenedioxy,aryloxy, cycloalkoxy, heteroaryloxy, alkylthio, haloalkylthio andcarboxyl. The alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, andheteroaryl moieties of any of the above substituents may be optionallysubstituted by one or more groups independently selected from: alkyl,haloalkyl, nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl,alkoxy, haloalkoxy, mercapto, alkylthio, haloalkylthio or arylthiogroups.

If the substituents themselves are not compatible with the syntheticmethods of this invention, the substituent may be protected with asuitable protecting group that is stable to the reaction conditions usedin these methods. The protecting group may be removed at a suitablepoint in the reaction sequence of the method to provide a desiredintermediate or target compound. Suitable protecting groups and themethods for protecting and de-protecting different substituents usingsuch suitable protecting groups are well known to those skilled in theart; examples of which may be found in T. Greene and P. Wuts, ProtectiveGroups in Organic Synthesis(3^(rd ed.), John Wiley & Sons, New York ()1999), which is incorporatedherein by reference in its entirety. In some instances, a substituentmay be specifically selected to be reactive under the reactionconditions used in the methods of this invention. Under thesecircumstances, the reaction conditions convert the selected substituentinto another substituent that is either useful in an intermediatecompound in the methods of this invention or is a desired substituent ina target compound.

In the compounds of this invention, R² and R^(2′), independently ortaken together, may be a suitable nitrogen protecting group. Asindicated above, nitrogen protecting groups are well known in the artand any nitrogen protecting group that is useful in the methods ofpreparing the compounds of this invention or may be useful in the HIVprotease inhibitory compounds of this invention may be used. Exemplarynitrogen protecting groups include alkyl, substituted alkyl, carbamate,urea, amide, imide, enamine, sulfenyl, sulfonyl, nitro, nitroso, oxide,phosphinyl, phosphoryl, silyl, organometallic, borinic acid and boronicacid groups. Examples of each of these groups, methods for protectingnitrogen moieties using these groups and methods for removing thesegroups from nitrogen moieties are disclosed in T. Greene and P. Wuts,supra. Preferably, when R² and/or R^(2′) are independently suitablenitrogen protecting groups, suitable R² and R^(2′) substituents include,but are not limited to, carbamate protecting groups such asalkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl) and aryloxycarbonyl(e.g., Cbz: benzyloxycarbonyl, or FMOC: fluorene-9-methyloxycarbonyl),alkyloxycarbonyls (e.g., methyloxycarbonyl), alkyl or arylcarbonyl,substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl),benzyl and substituted benzyl), and the like. When R² and R^(2′) takentogether are a suitable nitrogen protecting group, suitable R²/R^(2′)substituents include phthalimido and a stabase (1,2-bis(dialkylsilyl))ethylene).

The terms “halogen” and “halo” represent chloro, fluoro, bromo or iodosubstituents. “Heterocycle” is intended to mean a heteroaryl orheterocycloalkyl group. “Acyl@ is intended to mean a —C(O)—R radical,where R is a substituted or unsubstituted alkyl, cycloalkyl, aryl,heterocycloalkyl or heteroaryl group. “Acyloxy” is intended to mean an—OC(O)—R radical, where R is a substituted or unsubstituted alkyl,cycloalkyl, aryl, heterocycloalkyl or heteroaryl group. “thioacyl” isintended to mean a —C(S)—R radical, where R is a substituted orunsubstituted alkyl, cycloalkyl, aryl, heterocycloalkyl or heteroarylgroup. “Sulfonyl” is intended to mean an —SO₂-biradical. “Sulfenyl” isintended to mean an —SO— biradical. “Sulfo” is intended to mean an —SO₂Hradical. “Hydroxy” is intended to mean the radical —OH. “Amine” or“amino” is intended to mean the radical —NH₂. “Alkylamino” is intendedto mean the radical —NHR_(a), where R_(a) is an alkyl group.“Dialkylamino” is intended to mean the radical —NR_(a)R_(b), where R_(a)and R_(b) are each independently an alkyl group, and is intended toinclude heterocycloalkyl groups, wherein R_(a) and R_(b), takentogether, form a heterocyclic ring that includes the amine nitrogen.“Alkoxy” is intended to mean the radical —OR_(a), where R_(a) is analkyl group. Exemplary alkoxy groups include methoxy, ethoxy, propoxy,and the like. “Lower alkoxy” groups have alkyl moieties having from 1 to4 carbons. “Alkoxycarbonyl” is intended to mean the radical —C(O)OR_(a),where R_(a) is an alkyl group. “Alkylsulfonyl” is intended to mean theradical —SO₂R_(a), where R_(a) is an alkyl group. “Alkylenedioxy” isintended to mean the divalent radical —OR_(a)O— which is bonded toadjacent atoms (e.g., adjacent atoms on a phenyl or naphthyl ring),wherein R_(a) is a lower alkyl group. “Alkylaminocarbonyl” is intendedto mean the radical —C(O)NHR_(a), where R_(a) is an alkyl group.“Dialkylaminocarbonyl” is intended to mean the radical —C(O)NR_(a)R_(b),where R_(a) and R_(b) are each independently an alkyl group. “Mercapto”is intended to mean the radical —SH. “Alkylthio” is intended to mean theradical —SR_(a), where R_(a) is an alkyl group. “Carboxy” is intended tomean the radical —C(O)OH. “Keto” or “oxo” is intended to mean thediradical ═O.

“Thioketo” is intended to mean the diradical ═S. “Carbamoyl” is intendedto mean the radical —C(O)NH₂. “Cycloalkylalkyl” is intended to mean theradical Balkyl-cycloalkyl, wherein alkyl and cycloalkyl are defined asabove, and is represented by the bonding arrangement present in thegroups —CH₂-cyclohexane or —CH₂-cyclohexene. “Arylalkyl” is intended tomean the radical Balkylaryl, wherein alkyl and aryl are defined asabove, and is represented by the bonding arrangement present in a benzylgroup. “Aminocarbonylalkyl” is intended to mean the radical BalkylC(O)NH₂ and is represented by the bonding arrangement present in the group—CH₂CH₂C(O)NH₂. “Alkylaminocarbonylalkyl” is intended to mean theradical BalkylC(O)NHR_(a), where R_(a) is an alkyl group and isrepresented by the bonding arrangement present in the group—CH₂CH₂C(O)NHCH₃. “Alkylcarbonylaminoalkyl” is intended to mean theradical BalkylNHC(O)-alkyl and is represented by the bonding arrangementpresent in the group —CH₂NHC(O)CH₃. “Dialkylaminocarbonylalkyl” isintended to mean the radical BalkylC(O)NR_(a)R_(b), where R_(a) andR_(b) are each independently an alkyl group. “Aryloxy” is intended tomean the radical —OR_(c), where R_(c) is an aryl group. “Heteroaryloxy”is intended to mean the radical —OR_(d), where R_(d) is a heteroarylgroup. “Arylthio” is intended to mean the radical —SR_(c), where R_(c)is an aryl group. If an inventive compound is a base, a desired salt maybe prepared by any suitable method known in the art, including treatmentof the free base with an inorganic acid, such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, maleic acid,succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid,oxalic acid, glycolic acid, salicylic acid, pyranosidyl acid, such asglucuronic acid or galacturonic acid, alpha-hydroxy acid, such as citricacid or tartaric acid, amino acid, such as aspartic acid or glutamicacid, aromatic acid, such as benzoic acid or cinnamic acid, sulfonicacid, such as p-toluenesulfonic acid or ethanesulfonic acid, or thelike.

If an inventive compound is an acid, a desired salt may be prepared byany suitable method known to the art, including treatment of the freeacid with an inorganic or organic base, such as an amine (primary,secondary, or tertiary); an alkali metal or alkaline earth metalhydroxide; or the like. Illustrative examples of suitable salts includeorganic salts derived from amino acids such as glycine and arginine;ammonia; primary, secondary, and tertiary amines; and cyclic amines,such as piperidine, morpholine, and piperazine; as well as inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

Specific embodiments of the compounds of this invention comprising thecompounds depicted by Formula I may also be described. For example, thisinvention relates to compounds useful for inhibiting the activity ofHIV-protease of Formula I, above, wherein:

R¹ is a 5- or 6-membered monocyclic cycloalkyl, cycloalkenyl, aryl,heterocycloalkyl, heterocycloalkenyl or heteroaryl group, where saidcycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl orheteroaryl group is unsubstituted or substituted with one or moresubstituents independently selected from alkyl, haloalkyl, amino, cyano,halogen, hydroxyl, alkoxy, haloalkoxy, alkylenedioxy,di-haloalkylenedioxy, aryloxy, cycloalkoxy, cycloalkylalkoxy,cycloalkenyloxy, cycloalkenylalkoxy, heterocycloalkoxy,heterocycloalkylalkoxy, heterocycloalkenyloxy, heterocycloalkenylalkoxy,heteroaryloxy, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,alkylamino, dialkylamino, keto, alkylsulfonyl, arylsulfonyl,alkylcarbonylamino, alkylthio, haloalkylthio and arylthio, wherein anyof the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroarylmoieties present in the above substituents may be further substituted byone or more groups independently selected from alkyl, haloalkyl, aryl,nitro, amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy,haloalkoxy, aryloxy, mercapto, alkylthio, haloalkylthio and arylthiogroups;

R² is a substituted alkyl group, a substituted or unsubstituted alkenylgroup, or a substituted or unsubstituted alkynyl group, wherein saidalkyl, alkenyl or alkynyl group is a straight or branched chained group,and

where said substituted alkyl, alkenyl or alkynyl group is substituted byone or more substituents independently selected from amino, cyano,halogen, hydroxyl, alkoxy, haloalkoxy, aryloxy, cycloalkoxy,cycloalkylalkoxy, cycloalkenyloxy, cycloalkenylalkoxy,heterocycloalkoxy, heterocycloalkylalkoxy, heterocycloalkenyloxy,heterocycloalkenlalkoxy, heteroaryloxy, alkylamino, dialkylamino,alkylsulfonyl, arylsulfonyl, alkylsulfenyl, arylsulfenyl, alkylthio,haloalkylthio, arylthio and heteroarylthio groups, wherein any of thealkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkenyl, heteroaryl moieties present in theabove substituents may be further substituted by one or more groupsindependently selected from alkyl, haloalkyl, halogen, hydroxyl, alkoxy,haloalkoxy, alkylthio and haloalkylthio groups;

R^(2′) is H, methyl, ethyl or propyl, where said methyl, ethyl or propylis unsubstituted or substituted by halo or hydroxyl;

X is

wherein R^(x) is H or one or more substituents independently selectedfrom halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl,alkylenedioxy, di-haloalkylenedioxy, alkylamino, dialkylamino, alkylthioand haloalkylthio;

Z is S, O, SO, SO₂, CH₂ or CFH;

R³ is H;

R⁴, R⁵, R⁶ and R⁷ are independently selected from H or methyl; and

R⁸ and R^(8′) are independently selected from H, halogen, methyl,monohalo-methyl, dihalo-methyl and tri-halomethyl;

or a prodrug, pharmaceutically active metabolite or pharmaceuticallyactive salt or solvate thereof.

In more specific embodiments, this invention relates to compounds ofFormula I, above, wherein:

R¹ is phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl,tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl, where saidphenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl,tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl isunsubstituted or substituted with one or more substituents independentlyselected from alkyl, haloalkyl, halogen, and hydroxyl;

R² is a substituted alkyl group, a substituted or unsubstituted C₁-C₆alkenyl group, or a substituted or unsubstituted C₁-C₆ alkynyl group,wherein said alkyl, alkenyl or alkynyl group is a straight or branchedchained group, and

where said substituted alkyl, alkenyl or alkynyl group is substituted byone or more substituents independently selected from cyano, halogen andalkylamino;

R^(2′) is H, methyl or ethyl;

X is

wherein R^(x) is H, halogen, or alkoxy;

Z is S, O, CH₂ or CFH;

R³, R⁴, R⁵, R⁸ and R^(8′) are each H; and

R⁶ and R⁷ are independently selected from H or methyl;

or a prodrug, pharmaceutically active metabolite or pharmaceuticallyactive salt or solvate thereof.

In preferred specific embodiments, this invention relates to compoundsof Formula I, above, wherein:

R¹ is phenyl, where said phenyl is substituted with one or moresubstituents independently selected from alkyl, halogen or hydroxyl;

R² is a C₁-C₆ alkenyl group or a C₁-C₆ alkynyl group, wherein saidalkenyl or alkynyl group is a straight or branched chained group, and

where said alkenyl or alkynyl group is unsubstituted or is substitutedby one or more halogen substituents;

R^(2′) is H;

X is

wherein R^(x) is H;

Z is S;

R³, R⁴, R⁵, R⁸ and R^(8′) are each H; and

R⁶ and R⁷ are each methyl;

or a prodrug, pharmaceutically active metabolite or pharmaceuticallyactive salt or solvate thereof.

More specifically, this invention relates to compounds useful forinhibiting the activity of HIV-protease of Formula I, above, wherein:

R¹ is a 5- or 6-membered mono-cyclic cycloalkyl, cycloalkenyl, aryl,heterocycloalkyl, heterocycloalkenyl or heteroaryl group, where saidcycloalkyl, cycloalkenyl, aryl, heterocycloalkyl, heterocycloalkenyl orheteroaryl group is unsubstituted or substituted with one or moresubstituents independently selected from alkyl, haloalkyl, amino, cyano,halogen, hydroxyl, alkoxy, haloalkoxy, alkylenedioxy,dihaloalkylenedioxy, aryloxy, cycloalkoxy, cycloalkylalkoxy,cycloalkenyloxy, cycloalkenylalkoxy, heterocycloalkoxy,heterocycloalkylalkoxy, heterocycloalkenyloxy, heterocycloalkenylalkoxy,heteroaryloxy, alkylcarbonyloxy, arylcarbonyloxy, heteroarylcarbonyloxy,alkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl,alkylcarbonylamino, alkylthio, haloalkylthio and arylthio, wherein anyof the alkyl, alkylene, aryl, cycloalkyl, heterocycloalkyl, heteroarylmoieties present in the above substituents are substituted by one ormore groups independently selected from alkyl, haloalkyl, aryl, nitro,amino, alkylamino, dialkylamino, halogen, hydroxyl, alkoxy, haloalkoxy,aryloxy, mercapto, alkylthio, haloalkylthio and arylthio groups;

R² is a substituted phenyl group, a substituted phenylalkyl group, asubstituted or unsubstituted phenylalkenyl group or a substituted orunsubstituted phenylalkynyl group;

where said alkyl, alkenyl or alkynyl moiety of said phenylalkyl,phenylalkenyl or phenylalkynyl group is a straight or branched chainmoiety;

R^(2′) is H, methyl, ethyl or propyl, where said methyl, ethyl or propylis unsubstituted or substituted with halo or hydroxyl;

X is

wherein R^(x) is H or one or more substituents independently selectedfrom halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl,alkylenedioxy, di-haloalkylenedioxy, alkylamino, dialkylamino, alkylthioand haloalkylthio;

Z is S, O, SO, SO₂, CH₂ or CFH;

R³ is H;

R⁴, R⁵, R⁶ and R⁷ are independently selected from H or methyl; and

R⁸ and R^(8′) are independently selected from H, halogen, methyl,monohalo-methyl, dihalo-methyl and tri-halomethyl;

provided that said 5- or 6-membered mono-cyclic heterocycloalkyl,heterocycloalkenyl or heteroaryl group contains at least twoheteroatoms; or

provided that said alkyl, alkenyl or alkynyl moiety of said substitutedphenylalkyl, phenylalkenyl or phenylalkynyl group is substituted by oneor more substituents selected from halo or keto; or

provided that said substituted phenyl group or phenyl moiety of saidsubstituted phenylalkyl, phenylalkenyl or phenylalkynyl group issubstituted by one or more substituents other than halo or methyl, wheresaid one or more substituents is independently selected from haloalkyl,hydroxyalkyl, alkoxyalkyl, cycloalkoxyalkyl, alkylcarbonylalkyl,haloalkoxyalkyl, aryloxyalkyl, alkylthioalkyl, haloalkylthioalkyl,arylthioalkyl, cyanoalkyl, aminoalkyl, alkylaminoalkyl, alkenyl,alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkenyl, heteroaryl, nitro, amino, cyano, hydroxyl, alkoxy,haloalkoxy, alkenyloxy, alkynyloxy, alkylenedioxy, aryloxy, cycloalkoxy,cycloalkylalkoxy, cycloalkenyloxy, cycloalkenylalkoxy,heterocycloalkoxy, heterocycloalkylalkoxy, heterocycloalkenoxy,heterocycloalkenylalkoxy, heteroaryloxy, alkylcarbonyl,alkyloxycarbonyl, alkylcarbonyloxy, arylcarbonyl, arylcarbonyloxy,aryloxycarbonyl, cycloalkylcarbonyl, cycloalkylcarbonyloxy,cycloalkyoxycarbonyl, heteroarylcarbonyl, heteroarylcarbonyloxy,heteroaryloxycarbonyl, heterocycloalkylcarbonyl,heterocycloalkylcarbonyloxy, heterocycloalkyoxycarbonyl, carboxyl,carbamoyl, formyl, keto, thioketo, sulfo, alkylamino, cycloalkylamino,arylamino, heterocycloalkylamino, heteroarylamino, dialkylamino,alkylaminocarbonyl, cycloalkylaminocarbonyl, arylaminocarbonyl,heterocycloalkylaminocarbonyl, heteroarylaminocarbonyl,dialkylaminocarbonyl, alkylaminothiocarbonyl,cycloalkylaminothiocarbonyl, arylaminothiocarbonyl,heterocycloalkylaminothiocarbonyl, heteroarylaminothiocarbonyl,dialkylaminothiocarbonyl, alkylsulfonyl, arylsulfonyl, alkylsulfenyl,arylsulfenyl, alkylcarbonylamino, cycloalkylcarbonylamino,arylcarbonylamino, heterocycloalkylcarbonylamino,heteroarylcarbonylamino, alkylthiocarbonylamino,cycloalkylthiocarbonylamino, arylthiocarbonylamino,heterocycloalkylthiocarbonylamino, heteroarylthiocarbonylamino,alkylsulfonyloxy, arylsulfonyloxy, alkylsulfonylamino,arylsulfonylamino, mercapto, alkylthio, haloalkylthio, arylthio andheteroarylthio groups, wherein any of the alkyl, alkylene, aryl,cycloalkyl, heterocycloalkyl, or heteroaryl moieties present in theabove substituents are unsubstituted or substituted by one or moregroups independently selected from alkyl, haloalkyl, halogen, hydroxyl,alkoxy, haloalkoxy, alkylthio and haloalkylthio groups;

or a prodrug, pharmaceutically active metabolite or pharmaceuticallyactive salt or solvate thereof. If the phenyl group or phenyl moiety ofR² contains more than one substituent, the substituents may be the sameor different, and may be independently selected from the above-describedsubstituents.

More specifically, this invention relates to compounds useful forinhibiting the activity of HIV-protease of Formula I, above, wherein:

R¹ is phenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl,tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl, where saidphenyl, pyrrolyl, pyrrolidinyl, isoxazolyl, pyrazolyl, thiazolyl,tetrahydrofuranyl, furanyl, thienyl or tetrahydropyridazinyl isunsubstituted or substituted with one or more substituents independentlyselected from alkyl, haloalkyl, halogen, and hydroxyl;

R² is a substituted phenylalkyl group, where said alkyl moiety of saidsubstituted phenylalkyl group is a straight or branched chain alkylmoiety;

R^(2′) is H, methyl, ethyl or propyl, where said methyl, ethyl or propylis unsubstituted or substituted with hydroxyl;

X is

wherein R^(x) is H, halogen, or alkoxy;

Z is S, O, CH₂ or CFH;

R³, R⁴, R⁵, R⁸ and R^(8′) are each H; and

R⁶ and R⁷ are independently selected from H or methyl;

provided that R¹ is selected from isoxazolyl, pyrazolyl, thiazolyl ortetrahydropyridazinyl, where said is isoxazolyl, pyrazolyl, thiazolyl ortetrahydropyridazinyl is unsubstituted or substituted with one or moresubstituents independently selected from alkyl, haloalkyl, halogen, andhydroxyl when R² is a substituted or unsubstituted phenylalkyl group or

provided that R¹ is selected from phenyl, pyrrolyl, pyrrolidinyl,isoxazolyl, pyrazolyl, thiazolyl, tetrahydrofuranyl, furanyl, thienyl ortetrahydropyridazinyl when R² is a substituted phenylalkyl group andsaid phenyl moiety of said substituted phenylalkyl group comprises oneor more substituents other than halo or methyl, where said one or moresubstituents is independently selected from haloalkyl, amino, hydroxyl,alkoxy, haloalkoxy, alkylenedioxy, di-haloalkylenedioxy,cycloalkylalkyloxy, dialkylamino, alkylsulfonyl and alkylthio;

or a prodrug, pharmaceutically active metabolite or pharmaceuticallyactive salt or solvate thereof.

In preferred embodiments, this invention relates to compounds of FormulaI, above, wherein:

R¹ is phenyl, where said phenyl is substituted with one or moresubstituents independently selected from methyl, halogen or hydroxyl;

R² is a substituted phenylalkyl group, where said alkyl moiety of saidsubstituted phenylalkyl group is a straight or branched chain alkymoiety;

where said phenyl moiety of said substituted phenylalkyl group comprisesone or more substituents other than halo or methyl, where said one ormore substituents is independently selected from trifluoromethyl, amino,hydroxyl, C₁-C₄alkoxy, alkylenedioxy, di-fluoro-alkylenedioxy,cyclopropylmethoxy, di-methyl-amino, methanesulfonyl and methylthio;

R^(2′) is H, methyl or ethyl;

X is

wherein R^(x) is H;

Z is S or O; and

R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R^(8′) are each H;

or a prodrug, pharmaceutically active metabolite or pharmaceuticallyactive salt or solvate thereof.

All compounds of this invention contain at least one chiral center andmay exist as single stereoisomers (e.g., single enantiomers or singlediastereomers), any mixture of stereosisomers (e.g., any mixture ofenantiomers or diastereomers) or racemic mixtures thereof. All suchsingle stereoisomers, mixtures and racemates are intended to beencompassed within the broad scope of the present invention. Compoundsidentified herein as single stereoisomers are meant to describecompounds that are present in a form that contains at least 90% of asingle stereoisomer of each chiral center present in the compounds.Where the stereochemistry of the chiral carbons present in the chemicalstructures illustrated herein is not specified, the chemical structureis intended to encompass compounds containing either stereoisomer ofeach chiral center present in the compound. Preferably, however, theinventive compounds are used in optically pure, that is,stereoisomerically pure, form or substantially optically pure(substantially stereoisomerically pure) form. As used herein, the term“stereoisomeric” purity (or “optical” purity) refers to the“enantiomeric” purity and/or “diastereomeric” purity of a compound.Compounds that are substantially enantiomerically pure contain at least90% of a single isomer and preferably contain at least 95% of a singleisomer of each chiral center present in the enantiomer. Compounds thatare substantially diastereomerically pure contain at least 90% of asingle isomer of each chiral center present in the diastereomer, andpreferably contain at least 95% of a single isomer of each chiralcenter. More preferably, the substantially enantiomerically anddiastereomerically pure compounds in this invention contain at least97.5% of a single isomer and most preferably contain at least 99% of asingle isomer of each chiral center in the compound. The term Aracemic@or Aracemic mixture@ refers to a mixture of equal amounts ofenantiomeric compounds, which encompasses mixtures of enantiomers andmixtures of enantiomeric diastereomers. The compounds of this inventionmay be obtained in stereoisomerically pure (i.e., enantiomericallyand/or diastereomerically pure) or substantially stereoisomerically pure(i.e., substantially enantiomerically and/or diastereomerically pure)form. Such compounds may be obtained synthetically, according to theprocedures described herein using optically pure or substantiallyoptically pure materials. Alternatively, these compounds may be obtainedby resolution/separation of a mixture of stereoisomers, includingracemic mixtures, using conventional procedures. Exemplary methods thatmay be useful for the resolution/separation of stereoisomeric mixturesinclude chromatography and crystallization/re-crystallization. Otheruseful methods may be found in “Enantiomers, Racemates, andResolutions,” J. Jacques et al., 1981, John Wiley and Sons, New York,N.Y., the disclosure of which is incorporated herein by reference.Preferred stereoisomers of the compounds of this invention are describedherein.

Especially preferred embodiments of this invention comprise compounds,wherein the stereogenic centers (chiral carbons) have the followingdesignated stereochemistry:

More preferably, at least two of the stereogenic centers have thefollowing designated stereochemistry:

Even more preferably, at least three of the stereogenic centers have thefollowing designated stereochemistry:

Exemplary compounds of this invention include:

and the prodrugs, pharmaceutically active metabolites, andpharmaceutically acceptable salts and solvates thereof

The invention is also directed to the intermediates of Formula II, whichare useful in the synthesis of certain compounds of Formula I:

The present invention also provides processes for the preparation ofcompounds of formula (I-A), or a prodrug, pharmaceutically activemetabolite, or pharmaceutically active salt or solvate thereof,

wherein:

-   -   R¹ is a 5- or 6-membered mono-cyclic carbocyclic or heterocyclic        group, wherein said carbocyclic or heterocyclic group is        saturated, partially unsaturated or fully unsaturated and is        optionally substituted by at least one substituent chosen from        C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy, C₆₋₁₀        arylcarbonyloxy, and heteroarylcarbonyloxy;    -   R² is C₂₋₆ alkenyl or C₁₋₆ alkyl optionally substituted with at        least one halogen;    -   R^(2′) is H or C₁₋₄ alkyl;    -   Z is S, O, SO, SO₂, CH₂ or CFH;    -   R³ is H or C₁-C₄ alkyl; and    -   R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and C₁-C₆        alkyl;        comprising:

reacting a compound of formula (II), wherein Y¹ is hydroxyl or a leavinggroup, with a compound of formula (III), or a salt or solvate thereof.

In another aspect of the present invention are provided processes forthe preparation of compounds of formula (I-A), wherein in the compoundsof formula (II), Y¹ is hydroxyl.

In still another aspect of the present invention are provided processesfor the preparation of compounds of formula (I), wherein:

R¹ is phenyl optionally substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl or C₁₋₆ alkyl optionally substituted with at leastone halogen;

R^(2′) is H or C₁₋₄ alkyl;

Z is S, O, SO, SO₂, CH₂ or CFH;

R³ is H or C₁-C₄ alkyl; and

R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and methyl.

The present invention also provides processes for the preparation ofcompounds of formula (I), wherein:

R¹ is phenyl optionally substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl or C₁₋₆ alkyl optionally substituted with at leastone halogen;

R² is H or C₁₋₄ alkyl;

Z is S, O, SO, SO₂, CH₂ or CFH;

R³ is H or C₁-C₄ alkyl; and

R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and methyl.

In yet another aspect of the present invention are provides processesfor the preparation of compounds of formula (I-A), wherein:

R¹ is phenyl optionally substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl or C₁₋₆ alkyl optionally substituted with at leastone halogen;

R^(2′) is H;

Z is S, O, SO, or SO₂;

R³ is H or C₁-C₄ alkyl; and

R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and methyl.

Still another aspect of the present invention provides processes for thepreparation of compounds of formula (I-A), wherein:

R¹ is phenyl optionally substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl;

R^(2′) is H;

Z is S, O, SO, or SO₂;

R³ is H or C₁-C₄ alkyl; and

R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and methyl.

The present invention also provides provides processes for thepreparation of compounds of formula (I-A), wherein:

R¹ is phenyl optionally substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl;

R^(2′) is H;

Z is S or O;

R³ is H; and

R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and methyl.

In still a further aspect of the present invention are providedprocesses for the preparation of compounds of formula (I-A), wherein:

R¹ is phenyl optionally substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl;

R^(2′) is H;

Z is S;

R³ is H;

R⁴ and R⁵ are H; and

R⁶ and R⁷ are methyl.

In still a further aspect of the present invention are providedprocesses for the preparation of compounds of formula (I-A), wherein:

R¹ is phenyl substituted by at least one substituent independentlychosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy, C₆₋₁₀arylcarbonyloxy, and heteroarylcarbonyloxy;

R² is C₂₋₆ alkenyl;

R^(2′) is H;

Z is S;

R³ is H;

R⁴ and R⁵ are H; and

R⁶ and R⁷ are methyl.

The present invention also provides processes for the preparation ofcompounds of formula (I-A), wherein:

R¹ is phenyl substituted by C₁₋₆ alkyl and hydroxyl;

R² is allyl;

R^(2′) is H;

Z is S;

R³ is H;

R⁴ and R⁵ are H; and

R⁶ and R⁷ are methyl.

Furthermore, the present invention provides processes for thepreparation of compounds of formula (I-A), wherein:

R¹ is phenyl substituted by methyl and hydroxyl;

R² is allyl;

R^(2′) is H;

Z is S;

R³ is H;

R⁴ and R⁵ are H; and

R⁶ and R⁷ are methyl.

Another aspect of the present invention provides processes for thepreparation of compounds of formula (I-A), wherein the compound offormula (I-A) is:

In yet another aspect of the present invention are provided processesfor the preparation of compounds of formula (I-A), wherein:

R¹ is phenyl substituted by at least one substituent independentlychosen from C₁₋₆ alkyl and C₁₋₆ alkylcarbonyloxy;

R² is C₂₋₆ alkenyl;

R^(2′) is H;

Z is S;

R³ is H;

R⁴ and R⁵ are H; and

R⁶ and R⁷ are methyl.

The present invention further provides processes for the preparation ofcompounds of formula (I-A), wherein:

R¹ is phenyl substituted by methyl and methylcarbonyloxy;

R² is allyl;

R^(2′) is H;

Z is S;

R³ is H;

R⁴ and R⁵ are H; and

R⁶ and R⁷ are methyl.

Furthermore, the present invention provides processes for thepreparation of compounds of formula (I-A), wherein the compound offormula (I-A) is:

The present invention further provides processes for the preparation ofcompounds of formula (I-B),

comprising:

reacting a compound of formula (II-A) with a compound of formula(III-A), or a salt or solvate thereof.

The present invention further provides process for preparing a compoundof formula (I-C),

comprising:

(i) reacting a compound of formula (II-A) with a compound of formula(III-A), or a salt or solvate thereof,

to afford a compound of formula (I-B); and

(ii) deprotecting the compound of formula (I-B).

In yet another aspect of the present invention are provided processesfor preparing a compound of formula (I-C),

comprising:

reacting a compound of formula (II-B) with a compound of formula(III-A), or a salt or solvate thereof.

The present invention also provides processes for the preparation of acompound of formula (I-C),

comprising:

reacting a compound of formula (II-B) with a compound of formula(III-A), or a salt or solvate thereof.

In another aspect of the present invention are provided processes forpreparing a compound of formula (I-C),

comprising:

(i) reacting a compound of formula (IV-A) with a compound of formula(V-A),

to afford a compound of formula (II-A);

(ii) reacting the compound of formula (II-A) with a compound of formula(III-A), or a salt or solvate thereof,

to afford a compound of formula (I-B); and

(iii) deprotecting the compound of formula (I-B) to afford the compoundof formula (I-C).

The HIV protease inhibitor compounds of this invention include prodrugs,the pharmaceutically active metabolites, and the pharmaceuticallyacceptable salts and solvates thereof. In preferred embodiments, thecompounds of Formula I, prodrugs, pharmaceutically acceptable salts, andpharmaceutically active metabolites and solvates thereof demonstrate anHIV-protease inhibitory activity, corresponding to K_(i) of at least 100nM, an EC₅₀ of at least 10 mM or an IC₅₀ of at least 10 mM. Preferably,the compounds of this invention demonstrate an HIV-protease inhibitoryactivity, corresponding to a K_(i) of at least 10 nM, an EC₅₀ of atleast 1 mM or an IC₅₀ of at least 1 mM. More preferably, the compoundsof this invention demonstrate an HIV-protease inhibitory activityagainst mutant strains of HIV, corresponding to a K_(i) of at least 100nM, an EC₅₀ of at least 10 mM or an IC₅₀ of at least 10 mM. Even morepreferably, the compounds of this invention demonstrate proteaseinhibitory

activity against mutant strains corresponding to a K_(i) of at least 10nM, an EC₅₀ of at least 1 mM or an IC₅₀ of at least 1 mM.

A “prodrug” is intended to mean a compound that is converted underphysiological conditions or by solvolysis or metabolically to aspecified compound that is pharmaceutically active. A prodrug may be aderivative of one of the compounds of this invention that contains amoiety, such as for example —CO₂R, —PO(OR)₂ or —C═NR, that may becleaved under physiological conditions or by solvolysis. Any suitable Rsubstituent may be used that provides a pharmaceutically acceptablesolvolysis or cleavage product. A prodrug containing such a moiety maybe prepared according to conventional procedures by treatment of acompound of this invention containing, for example, an amido, carboxylicacid, or hydroxyl moiety with a suitable reagent. A “pharmaceuticallyactive metabolite” is intended to mean a pharmacologically activecompound produced through metabolism in the body of a specifiedcompound. Prodrugs and active metabolites of compounds of this inventionof the above-described Formulas may be determined using techniques knownin the art, for example, through metabolic studies. See, e.g., “Designof Prodrugs,” (Bundgaard, ed.), 1985, Elsevier Publishers B.V.,Amsterdam, The Netherlands. The following is an example of a prodrugthat can be converted to the compound of this invention underphysiological conditions, by solvolysis or metabolically:

A “pharmaceutically acceptable salt” is intended to mean a salt thatretains the biological effectiveness of the free acids and bases of aspecified compound and that is not biologically or otherwiseundesirable. Examples of pharmaceutically acceptable salts includesulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, y-hydroxybutyrates, glycollates, tartrates,methane-sulfonates (mesylates), propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates. A“solvate” is intended to mean a pharmaceutically acceptable solvate formof a specified compound that retains the biological effectiveness ofsuch compound. Examples of solvates include compounds of the inventionin combination with water, isopropanol, ethanol, methanol, DMSO, ethylacetate, acetic acid, or ethanolamine. In the case of compounds, salts,or solvates that are solids, it is understood by those skilled in theart that the inventive compounds, salts, and solvates may exist indifferent crystal forms, all of which are intended to be within thescope of the present invention and specified formulas.

The present invention is also directed to a method of inhibiting HIVprotease activity, comprising contacting the protease with an effectiveamount of a compound of Formula I, or a pharmaceutically acceptablesalt, prodrug, pharmaceutically active metabolite, or solvate thereof.For example, HIV protease activity may be inhibited in mammalian tissueby administering a compound of Formula I or a pharmaceuticallyacceptable salt, prodrug, pharmaceutically active metabolite, or solvatethereof. More preferably, the present method is directed at inhibitingHIV-protease activity. “Treating” or “treatment” is intended to mean atleast the mitigation of a disease condition in a mammal, such as ahuman, that is alleviated by the inhibition of the activity of HIVproteases. The methods of treatment for mitigation of a diseasecondition include the use of the compounds in this invention in anyconventionally acceptable manner, for example, as a prophylactic. Theactivity of the inventive compounds as inhibitors of HIV proteaseactivity may be measured by any of the suitable methods known to thoseskilled in the art, including in vivo and in vitro assays. Examples ofsuitable assays for activity measurements are described herein.Administration of the compounds of the Formula I and theirpharmaceutically acceptable prodrugs, salts, active metabolites, andsolvates may be performed according to any of the generally acceptedmodes of administration available to those skilled in the art.Illustrative examples of suitable modes of administration include oral,nasal, parenteral, topical, transdermal, and rectal.

An inventive compound of Formula I or a pharmaceutically acceptablesalt, prodrug, active metabolite, or solvate thereof may be administeredas a pharmaceutical composition in any pharmaceutical form recognizableto the skilled artisan as being suitable. Suitable pharmaceutical formsinclude solid, semisolid, liquid, or lyophilized formulations, such astablets, powders, capsules, suppositories, suspensions, liposomes, andaerosols. Pharmaceutical compositions of the invention may also includesuitable excipients, diluents, vehicles, and carriers, as well as otherpharmaceutically active agents, depending upon the intended use or modeof administration. Acceptable methods of preparing suitablepharmaceutical forms of the pharmaceutical compositions may be routinelydetermined by those skilled in the art. For example, pharmaceuticalpreparations may be prepared following conventional techniques of thepharmaceutical chemist involving steps such as mixing, granulating, andcompressing when necessary for tablet forms, or mixing, filling, anddissolving the ingredients as appropriate, to give the desired productsfor oral, parenteral, topical, intravaginal, intranasal, intrabronchial,intraocular, intraaural, and/or rectal administration.

The present invention includes pharmaceutical compositions useful forinhibiting HIV protease, comprising an effective amount of a compound ofthis invention, and a pharmaceutically acceptable carrier.Pharmaceutical compositions useful for treating infection by HIV, or fortreating AIDS or ARC, are also encompassed by the present invention, aswell as a method of inhibiting HIV protease, and a method of treatinginfection by HIV, or of treating AIDS or ARC. Additionally, the presentinvention is directed to a pharmaceutical composition comprising atherapeutically effective amount of a compound of the present inventionin combination with a therapeutically effective amount of an HIVinfection/AIDS treatment agent selected from:

-   -   1) an HIV/AIDS antiviral agent,    -   2) an anti-infective agent, and    -   3) an immunomodulator.

The compounds of the present invention may be administered incombination with an additional agent or agents for the treatment of amammal, such as a human, that is suffering from an infection with theHIV virus, AIDS, AIDS-related complex (ARC), or any other disease orcondition which is related to infection with the HIV virus. The agentsthat may be used in combination with the compounds of the presentinvention include, but are not limited to, those useful as HIV proteaseinhibitors, HIV reverse transcriptase inhibitors, non-nucleoside HIVreverse transcriptase inhibitors, inhibitors of HIV integrase, CCR5inhibitors, HIV fusion inhibitors, compounds useful as immunomodulators,compounds that inhibit the HIV virus by an unknown mechanism, compoundsuseful for the treatment of herpes viruses, compounds useful asanti-infectives, and others as described below.

Compounds useful as HIV protease inhibitors that may be used incombination with the compounds of the present invention include, but arenot limited to, 141 W94 (amprenavir), CGP-73547, CGP-61755, DMP-450,nelfinavir, ritonavir, saquinavir (invirase), lopinavir, TMC-126,BMS-232632 (atazanavir), palinavir, GS-3333, KN I-413, KNI-272,LG-71350, CGP-61755, PD 173606, PD 177298, PD 178390, PD 178392,U-140690, ABT-378, DMP-450, AG-1776, MK-944, VX-478, indinavir,tipranavir, TMC-114, DPC-681, DPC-684, fosamprenavir calcium (Lexiva),benzenesulfonamide derivatives disclosed in WO 03053435, R-944,Ro-03-34649, VX-385, GS-224338, OPT-TL3, PL-100, SM-309515, AG-148,DG-35-VIII, DMP-850, GW-5950X, KNI-1039, L-756423, LB-71262, LP-130,RS-344, SE-063, UIC-94-003, Vb-19038, A-77003, BMS-182193, BMS-186318,SM-309515, and JE-2147.

Compounds useful as inhibitors of the HIV reverse transcriptase enzymethat may be used in combination with the compounds of the presentinvention include, but are not limited to, abacavir (1592U89), FTC,GS-840, lamivudine (3TC), adefovir dipivoxil, beta-fluoro-ddA, ddC(dideoxycytidine, zalcitabine), ddl (dideoxyinsine, didanosine),stavudine (d4T), zidovudine (AZT), tenofovir, amdoxovir, SPD-754,SPD-756, racivir, reverset (DPC-817), MIV-210 (FLG), beta-L-Fd4C(ACH-126443), MIV-3 10 (alovudine, FLT), dOTC, DAPD, and emtricitabine.

Compounds useful as non-nucleoside inhibitors of the HIV reversetranscriptase enzyme include, but are not limited to, efavirenz,HBY-097, nevirapine, TMC-120 (dapivirine), TMC-125, delaviradine,DPC-083, DPC-961, TMC-120, capravirine, and tricyclic pyrimidinonederivatives as disclosed in WO 03062238.

Compounds useful as CCR5 inhibitors that may be used in combination withthe compounds of the present invention include, but are not limited to,TAK-779, SC-351125, SCH-D, UK-427857, PRO-140, and GW-873140 (Ono-4128,AK-602).

Compounds useful as inhibitors of HIV integrase enzyme that may be usedin combination with the compounds of the present invention include, butare not limited to, 1,5-naphthyridine-3-carboxamide derivativesdisclosed in WO 03062204, compounds disclosed in WO 03047564, compoundsdisclosed in WO 03049690, and 5-hydroxypyrimidine-4-carboxamidederivatives disclosed in WO 03035076.

Fusion inhibitors for the treatment of HIV that may be used incombination with the compounds of the present invention include, but arenot limited to, T20, T-1249, AMD-3100, and fused tricyclic compoundsdisclosed in JP 2003171381.

Other compounds that are useful inhibitors of HIV that may be used incombination with the compounds of the present invention include, but arenot limited to, Soluble CD4, TNX-355, PRO-542, BMS-806, tenofovirdisoproxil fumarate, and compounds disclosed in JP 2003119137.

Compounds useful in the treatment or management of infection fromviruses other than HIV that may be used in combination with thecompounds of the present invention include, but are not limited to,acyclovir, penciclovir, HPMPC, oxetanocin G, AL-721, cidofovir,cytomegalovirus immune globin, cytovene, ganciclovir, famciclovir, Isis2922, KNI-272, valaciclovir, and virazole ribavirin.

Compounds that act as immunomodulators and may be used in combinationwith the compounds of the present invention include, but are not limitedto, AD-439, AD-519, Alpha Interferon, AS-101, bropirimine, acemannan,CL246,738, EL10, FP-21399, gamma interferon, granulocyte macrophagecolony stimulating factor, IL-2, immune globulin intravenous, IMREG-1,IMREG-2, imuthiol diethyl dithio carbamate, alpha-2 interferon,methionine-enkephalin, MTP-PE, granulocyte colony stimulating sactor,remune, rCD4, recombinant soluble human CD4, interferon alfa-2,SK&F106528, soluble T4 yhymopentin, tumor necrosis factor (TNF),tucaresol, recombinant human interferon beta, and interferon alfa n-3.

Anti-infectives that may be used in combination with the compounds ofthe present invention include, but are not limited to, clindamycin withprimaquine, fluconazole, pastill, ornidyl, eflornithine pentamidine,spiramycin, intraconazole-R51211, trimetrexate, daunorubicin,recombinant human erythropoietin, recombinant human growth hormone,megestrol acetate, testerone, and total enteral nutrition.

Other compounds that may be used in combination with the compounds ofthe present invention include, but are not limited to, acmannan,ansamycin, LM 427, AR^(177,) BMS-232623, BMS-234475, CI-1012, curdlansulfate, dextran sulfate, STOCRINE EL10, hypericin, lobucavir, novapren,peptide T octabpeptide sequence, trisodium phosphonoformate, probucol,and RBC-CD4.

In addition, the compounds of the present invention may be used incombination with compounds that act as inhibitors of metallo-matrixproteases, so-called MMP inhibitors.

The particular choice of an additional agent or agents will depend on anumber of factors that include, but are not limited to, the condition ofthe mammal being treated, the particular condition or conditions beingtreated, the identity of the compound or compounds of the presentinvention and the additional agent or agents, and the identity of anyadditional compounds that are being used to treat the mammal. Theparticular choice of the compound or compounds of the invention and theadditional agent or agents is within the knowledge of one of ordinaryskill in the art.

The compounds of the present invention may be administered incombination with any of the above additional agents for the treatment ofa mammal, such as a human, that is suffering from an infection with theHIV virus, AIDS, AIDS-related complex (ARC), or any other disease orcondition which is related to infection with the HIV virus. Such acombination may be administered to a mammal such that a compound orcompounds of the present invention are present in the same formulationas the additional agents described above. Alternatively, such acombination may be administered to a mammal suffering from infectionwith the HIV virus such that the compound or compounds of the presentinvention are present in a formulation that is separate from theformulation in which the additional agent is found. If the compound orcompounds of the present invention are administered separately from theadditional agent, such administration may take place concomitantly orsequentially with an appropriate period of time in between. The choiceof whether to include the compound or compounds of the present inventionin the same formulation as the additional agent or agents is within theknowledge of one of ordinary skill in the art.

Additionally, the compounds of the present invention may be administeredto a mammal, such as a human, in combination with an additional agentthat has the effect of increasing the exposure of the mammal to acompound of the invention. The term “exposure,” as used herein, refersto the concentration of a compound of the invention in the plasma of amammal as measured over a period of time. The exposure of a mammal to aparticular compound can be measured by administering a compound of theinvention to a mammal in an appropriate form, withdrawing plasma samplesat predetermined times, and measuring the amount of a compound of theinvention in the plasma using an appropriate analytical technique, suchas liquid chromatography or liquid chromatography/mass spectroscopy. Theamount of a compound of the invention present in the plasma at a certaintime is determined and the concentration and time data from all thesamples are plotted to afford a curve. The area under this curve iscalculated and affords the exposure of the mammal to the compound. Theterms “exposure,” “area under the curve,” and “area under theconcentration/time curve” are intended to have the same meaning and maybe used interchangeably throughout.

Among the agents that may be used to increase the exposure of a mammalto a compound of the present invention are those that can as inhibitorsof at least one isoform of the cytochrome P450 (CYP450)enzymes. Theisoforms of CYP450 that may be beneficially inhibited include, but arenot limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4. Suitableagents that may be used to inhibit CYP 3A4 include, but are not limitedto, ritonavir.

Such a combination may be administered to a mammal such that a compoundor compounds of the present invention are present in the sameformulation as the additional agents described above. Alternatively,such a combination may be administered such that the compound orcompounds of the present invention are present in a formulation that isseparate from the formulation in which the additional agent is found. Ifthe compound or compounds of the present invention are administeredseparately from the additional agent, such administration may take placeconcomitantly or sequentially with an appropriate period of time inbetween. The choice of whether to include the compound or compounds ofthe present invention in the same formulation as the additional agent oragents is within the knowledge of one of ordinary skill in the art.

The present invention also includes the use of a compound of the presentinvention as described above in the preparation of a medicament for (a)inhibiting HIV protease, (b) preventing or treating infection by HIV, or(c) treating AIDS or ARC.

The present invention further includes the use of any of the HIVprotease inhibiting compounds of the present invention as describedabove in combination with one or more HIV infection/AIDS treatmentagents selected from an HIV/AIDS antiviral agent, an anti-infectiveagent, and an immunomodulator for the manufacture of a medicament for(a) inhibiting HIV protease, (b) preventing or treating infection byHIV, or (c) treating AIDS or ARC, said medicament comprising aneffective amount of the HIV protease inhibitor compound and an effectiveamount of the one or more treatment agents.

Solid or liquid pharmaceutically acceptable carriers, diluents,vehicles, or excipients may be employed in the pharmaceuticalcompositions. Illustrative solid carriers include starch, lactose,calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, pectin,acacia, magnesium stearate, and stearic acid. Illustrative liquidcarriers include syrup, peanut oil, olive oil, saline solution, andwater. The carrier or diluent may include a suitable prolonged-releasematerial, such as glyceryl monostearate or glyceryl distearate, alone orwith a wax. When a liquid carrier is used, the preparation may be in theform of a syrup, elixir, emulsion, soft gelatin capsule, sterileinjectable liquid (e.g., solution), or a nonaqueous or aqueous liquidsuspension. A dose of the pharmaceutical composition contains at least atherapeutically effective amount of the active compound (i.e., acompound of Formula I or a pharmaceutically acceptable salt, prodrug,active metabolite, or solvate thereof), and preferably is made up of oneor more pharmaceutical dosage units. The selected dose may beadministered to a mammal, for example, a human patient, in need oftreatment mediated by inhibition of HIV protease activity, by any knownor suitable method of administering the dose, including: topically (forexample, as an ointment or cream), orally, rectally (for example, as asuppository), parenterally (by injection) or continuously byintravaginal, intranasal, intrabronchial, intraaural, or intraocularinfusion. A “therapeutically effective amount” is intended to mean theamount of an inventive agent that, when administered to a mammal in needthereof, is sufficient to effect treatment for disease conditionsalleviated by the inhibition of the activity of one or more variant ofthe HIV protease. The amount of a given compound of the invention thatwill be therapeutically effective will vary depending upon factors suchas the particular compound, the disease condition and the severitythereof, the identity of the mammal in need thereof, which amount may beroutinely determined by artisans.

The compounds of this invention are also useful in the preparation andexecution of screening assays for antiviral compounds. For example, thecompounds of this invention are useful for isolating enzyme mutants thatare excellent screening tools for more powerful antiviral compounds.Furthermore, the compounds of this invention are useful in establishingor determining the binding site of other antivirals to HIV protease,e.g., by competitive inhibition. Thus the compounds of this inventionare commercial products to be sold for these purposes.

General Synthetic Methods

Compounds of formula (I-A),

wherein R¹ is a 5- or 6-membered mono-cyclic carbocyclic or heterocyclicgroup, wherein said carbocyclic or heterocyclic group is saturated,partially unsaturated or fully unsaturated and is substituted by atleast one hydroxyl, and Z, R², R^(2′), R³, R⁴, R⁵, R⁶, and are ashereinbefore defined, may be prepared from compounds of formula (I-A)wherein R¹ is a 5- or 6-membered mono-cyclic carbocyclic or heterocyclicgroup, wherein said carbocyclic or heterocyclic group is saturated,partially unsaturated or fully unsaturated and is substituted by atleast one substituent chosen from C₁₋₆ alkylcarbonyloxy, C₆₋₁₀arylcarbonyloxy, and heteroarylcarbonyloxy. The C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy groups may be cleavedunder conditions that directly provide the desired hydroxy substitutedcompounds of the invention. In general, the C₁₋₆ alkylcarbonyloxy, C₆₋₁₀arylcarbonyloxy, and heteroarylcarbonyloxy groups may be cleaved underbasic conditions, in a solvent that will not interfere with the desiredtransformation, and at a temperature that is compatible with the otherreaction parameters, all of which are known to those of ordinary skillin the art. For example, appropriate bases include, but are not limitedto, sodium bicarbonate, potassium bicarbonate, sodium carbonate,potassium carbonate, sodium hydroxide, potassium hydroxide, a sodiumalkoxide such as sodium methoxide or sodium ethoxide, a potassiumalkoxide such as potassium methoxide or potassium ethoxide, or a baseformed in situ using an appropriate combination of reagents, such as acombination of a trialkyl or aryl amine in combination with an alkanolsuch as methanol. Or such a transformation may be accomplished using anacid that is known to those of skill in the art to be appropriate tocleave such a group without interfering with the desired transformation.Such acids include, but are not limited to, hydrogen halides such ashydrochloric acid or hydroiodic acid, an alkyl sulfonic acid such asmethanesulfonic acid, an aryl sulfonic acid such as benzenesulfonicacid, nitric acid, sulfuric acid, perchloric acid, or chloric acid.Furthermore, appropriate solvents include those that are known to thoseof skill in the art to be compatible with the reaction conditions andinclude alkyl esters and aryl esters, alkyl, heterocyclic, and arylethers, hydrocarbons, alkyl and aryl alcohols, alkyl and arylhalogenated compounds, alkyl or aryl nitriles, alkyl and aryl ketones,and non-protic heterocyclic solvents. For example, suitable solventsinclude, but are not limited to, ethyl acetate, isobutyl acetate,isopropyl acetate, n-butyl acetate, methyl isobutyl ketone,dimethoxyethane, diisopropyl ether, chlorobenzene, dimethyl formamide,dimethyl acetamide, propionitrile, butyronitrile, t-amyl alcohol, aceticacid, diethyl ether, methyl-t-butyl ether, diphenyl ether, methylphenylether, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane,hexane, heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Finally, these transformations may be conducted attemperatures from −20° C. to 100° C., depending on the specificreactants and solvents and is within the skill of one of ordinary skillin the art. Further suitable reaction conditions may be found in T.Greene and P. Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.),John Wiley & Sons, NY (1999).

For example, the compound of Example A1 was prepared by cleaving anacetate protecting group using 4N hydrochloric acid in a mixture ofmethanol and 1,4-dioxane at room temperature.

Compounds of formula (I-A) wherein R³ is hydrogen and Z, R¹, R², R^(2′),R⁴, R⁵, R⁶, and R⁷, are as hereinbefore defined, may be prepared fromcompounds of formula (I-A) wherein R³ is a hydroxyl protecting group.The choice of a suitable hydroxy protecting group is within theknowledge of one of ordinary skill in the art. Suitable hydroxylprotecting groups that are useful in the present invention include, butare not limited to, alkyl or aryl esters, alkyl silanes, aryl silanes oralkylaryl silanes, alkyl or aryl carbonates, benzyl groups, substitutedbenzyl groups, ethers, or substituted ethers. The various hydroxyprotecting groups can be suitably cleaved utilizing a number of reactionconditions known to those of ordinary skill in the art. The particularconditions used will depend on the particular protecting group as wellas the other functional groups contained in the subject compound. Choiceof suitable conditions is within the knowledge of those of ordinaryskill in the art.

For example, if the hydroxy protecting group is an alkyl or aryl ester,cleavage of the protecting group may be accomplished using a suitablebase, such as a carbonate, a bicarbonate, a hydroxide, an alkoxide, or abase formed in situ from an appropriate combination of agents.Furthermore, such reactions may be performed in a solvent that iscompatible with the reaction conditions and will not interfere with thedesired transformation. For example, suitable solvents may include alkylesters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers,alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenatedsolvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones,alkylaryl ketones, or non-protic heterocyclic compounds. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Finally, such reactionsmay be performed at an appropriate temperature from −20° C. to 100° C.,depending on the specific reactants used. The choice of a suitabletemperature is within the knowledge of one of ordinary skill in the art.Further suitable reaction conditions may be found in T. Greene and P.Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.), John Wiley &Sons, NY (1999).

Additionally, if R³ is an alkyl silane, aryl silane or alkylaryl silane,such groups may be cleaved under conditions known to those of ordinaryskill in the art. For example, such silane protecting groups may becleaved by exposure of the subject compound to a source of fluorideions, such as the use of an organic fluoride salt such as atetraalkylammonium fluoride salt, or an inorganic fluoride salt.Suitable fluoride ion sources include, but are not limited to,tetramethylammonium fluoride, tetraethylammonium fluoride,tetrapropylammonium fluoride, tetrabutylammonium fluoride, sodiumfluoride, and potassium fluoride. Alternatively, such silane protectinggroups may be cleaved under acidic conditions using organic or mineralacids, with or without the use of a buffering agent. For example,suitable acids include, but are not limited to, hydrofluoric acid,hydrochloric acid, sulfuric acid, nitric acid, acetic acid, citric acid,and methanesulfonic acid. Such silane protecting groups may also becleaved using appropriate Lewis acids. For example, suitable Lewis acidsinclude, but are not limited to, dimethylbromo borane, triphenylmethyltetrafluoroborate, and certain Pd (II) salts. Such silane protectinggroups can also be cleaved under basic conditions that employappropriate organic or inorganic basic compounds. For example, suchbasic compounds include, but are not limited to, sodium carbonate,potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodiumhydroxide, and potassium hydroxide. The cleavage of a silane protectinggroup may be conducted in an appropriate solvent that is compatible withthe specific reaction conditions chosen and will not interfere with thedesired transformation. Among such suitable solvents are, for example,alkyl esters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers,alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenatedsolvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones,alkylaryl ketones, or non-protic heterocyclic compounds. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Finally, such reactionsmay be performed at an appropriate temperature from −20° C. to 100° C.,depending on the specific reactants used. The choice of a suitabletemperature is within the knowledge of one of ordinary skill in the art.Further suitable reaction conditions may be found in T. Greene and P.Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.), John Wiley &Sons, NY (1999).

When R³ is a benzyl or substituted benzyl ether, cleavage of theprotecting group may be accomplished by treating the subject compoundwith hydrogen in the presence of a suitable catalyst, oxidation withsuitable compounds, exposure to light of particular wavelengths,electrolysis, treatment with protic acids, or treatment with Lewisacids. The choice of particular reagents to effect such a transformationwill depend on the specific subject compound used and is within theskill of one of ordinary skill in the art. For example, such benzyl orsubstituted benzyl ethers may be cleaved using hydrogen gas in thepresence of an appropriate catalyst. Suitable catalysts include, but arenot limited to, 5% palladium on carbon, 10% palladium on carbon, 5%platinum on carbon, or 10% platinum on carbon. The choice of aparticular catalyst and the amounts of catalyst, the amount of hydrogengas, and the hydrogen gas pressure used to effect the desiredtransformation will depend upon the specific subject compound and theparticular reaction conditions utilized. Such choices are within theskill of one of ordinary skill in the art. Furthermore, such benzyl andsubstituted benzyl ethers may be cleaved under oxidative conditions inwhich a suitable amount of an oxidizer is used. Such suitable oxidizersinclude, but are not limited to, dichlorodicyanoquinone (DDQ), cericammonium nitrate (CAN), ruthenium oxide in combination with sodiumperiodate, iron (III) chloride, or ozone. Additionally, such ethers maybe cleaved using an appropriate Lewis acid. Such suitable Lewis acidsinclude, but are not limited to, dimethylbromo borane, triphenylmethyltetrafluoroborate, sodium iodide in combination withtrifluoroborane-etherate, trichloroborane, or tin (IV) chloride. Thecleavage of a benzyl or substituted benzyl ether protecting group may beconducted in an appropriate solvent that is compatible with the specificreaction conditions chosen and will not interfere with the desiredtransformation. Among such suitable solvents are, for example, alkylesters, alkylaryl esters, aryl esters, alkyl ethers, aryl ethers,alkylaryl esters, cyclic ethers, hydrocarbons, alcohols, halogenatedsolvents, alkyl nitriles, aryl nitriles, alkyl ketones, aryl ketones,alkylaryl ketones, or non-protic heterocyclic compounds. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Finally, such reactionsmay be performed at an appropriate temperature from −20° C. to 100° C.,depending on the specific reactants used. The choice of a suitabletemperature is within the knowledge of one of ordinary skill in the art.Further suitable reaction conditions may be found in T. Greene and P.Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.), John Wiley &Sons, NY (1999).

When R³ is methyl, cleavage of the protecting group may be accomplishedby treating the subject compound with organic or inorganic acids orLewis acids. The choice of a particular reagent will depend upon thetype of methyl ether present as well as the other reaction conditions.The choice of a suitable reagent for cleaving a methyl ether is withinthe knowledge of one of ordinary skill in the art. Examples of suitablereagents include, but are not limited to, hydrochloric acid, sulfuricacid, nitric acid, para-toluenesulfonic acid, or Lewis acids such asboron trifluoride etherate. These reactions may be conducted in solventsthat are compatible with the specific reaction conditions chosen andwill not interfere with the desired transformation. Among such suitablesolvents are, for example, alkyl esters, alkylaryl esters, aryl esters,alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers,hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, arylnitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-proticheterocyclic compounds. For example, suitable solvents include, but arenot limited to, ethyl acetate, isobutyl acetate, isopropyl acetate,n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropylether, chlorobenzene, dimethyl formamide, dimethyl acetamide,propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethylether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Finally, such reactions may be performed at an appropriatetemperature from −20° C. to 100° C., depending on the specific reactantsused. The choice of a suitable temperature is within the skill of one ofordinary skill in the art. Further suitable reaction conditions may befound in T. Greene and P. Wuts, Protective Groups in Organic Synthesis(3^(rd) ed.), John Wiley & Sons, NY (1999).

When R³ is a carbonate, cleavage of the protecting group may beaccomplished by treating the subject compound with suitable basiccompounds Such suitable basic compounds may include, but are not limitedto, sodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, sodium hydroxide, or potassium hydroxide. The choice of aparticular reagent will depend upon the type of carbonate present aswell as the other reaction conditions. These reactions may be conductedin solvents that are compatible with the specific reaction conditionschosen and will not interfere with the desired transformation. Amongsuch suitable solvents are, for example, alkyl esters, alkylaryl esters,aryl esters, alkyl ethers, aryl ethers, alkylaryl esters, cyclic ethers,hydrocarbons, alcohols, halogenated solvents, alkyl nitriles, arylnitriles, alkyl ketones, aryl ketones, alkylaryl ketones, or non-proticheterocyclic compounds. For example, suitable solvents include, but arenot limited to, ethyl acetate, isobutyl acetate, isopropyl acetate,n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropylether, chlorobenzene, dimethyl formamide, dimethyl acetamide,propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethylether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Finally, such reactions may be performed at an appropriatetemperature from −20° C. to 100° C., depending on the specific reactantsused. The choice of a suitable temperature is within the knowledge ofone of ordinary skill in the art. Further suitable reaction conditionsmay be found in T. Greene and P. Wuts, Protective Groups in OrganicSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999).

Furthermore, compounds of formula I wherein R¹ is phenyl substituted byat least one group selected from hydroxy, and R³ is hydrogen, may beprepared from compounds of formula I wherein R¹ is phenyl optionallysubstituted by at least one substituent independently chosen from C₁₋₆alkylcarbonyloxy, C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy; andR³ is a hydroxyl protecting group. In these compounds, the R¹ C₁₋₆alkylcarbonyloxy, C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy groupand the R³ hydroxyl protecting group may be removed using reactionsconditions in which both groups are removed concomitantly or they may beremoved in step-wise fashion. For example, when R¹ is phenyl substitutedby alkylcarbonyloxy and R³ is an alkyl ester, both groups may be cleavedby reacting the subject compound with a base in an appropriate solventand at an appropriate temperature. The choice of a suitable base,solvent, and temperature will depend on the particular subject compoundand the particular protecting groups being utilized. These choices arewithin the skill of one of ordinary skill in the art. For example, incompound (1), wherein R¹ is phenyl substituted with methylcarbonyloxyand methyl and R³ is acetoxy, the methylcarbonyl and acetoxy protectinggroups were cleaved concomitantly upon reacting (1) with potassiumhydroxide in a mixture of methanol and acetonitrile to afford thedesired compound, as shown below.

Alternatively, in compounds of formula (I-A) wherein R¹ is phenylsubstituted by at least one group selected from C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy, and R³ is a hydroxylprotecting group, the C₁₋₆ alkylcarbonyloxy, C₆₋₁₀ arylcarbonyloxy, andheteroarylcarbonyloxy group and the R³ hydroxyl protecting group may becleaved in a stepwise manner to afford a compound of formula I whereinR¹ is phenyl substituted by hydroxy and R³ is hydrogen. The choice ofthe R³ hydroxyl protecting group and the conditions to affect itscleavage will depend upon the specific subject compound chosen and iswithin the knowledge of one of ordinary skill in the art. For example,in the compounds of formula (I-A) wherein R¹ is phenyl substituted byC₁₋₆ alkylcarbonyloxy and R³ is a silane protecting group, the R³ silaneprotecting group may be cleaved first by treatment of the subjectcompound with a fluoride source such as tetrabutylammonium fluoride inacetonitrile at room temperature, followed by cleavage of the C₁₋₆alkylcarbonyloxy group in R¹ by treatment with a base such as potassiumhydroxide in a mixture of methanol and acetonitrile at room temperature.

Compounds of formula (I-A) wherein Z, R¹, R², R^(2′), R³, R⁴, R⁵, R⁶,and R⁷, are as hereinbefore defined may be prepared by reacting acompound of formula (II), wherein Y¹ is a leaving group and R¹ and R³are as hereinbefore defined,

with a compound of formula (III),

wherein Z, R², R^(2′), R⁴, R⁵, R⁶ and R⁷ are as hereinbefore defined, ora salt or solvate thereof, to afford a compound of formula (I-A).

In general, these reactions may be performed in a solvent that does notinterfere with the reaction, for example alkyl or aryl ethers, alkyl oraryl esters, aromatic and aliphatic hydrocarbons, non-competitivealcohols, halogenated solvents, alkyl or aryl nitriles, alkyl or arylketones, aromatic hydrocarbons, or heteroaromatic hydrocarbons. Forexample, suitable solvents include, but are not limited to, ethylacetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene,dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile,t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether,diphenyl ether, methylphenyl ether, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane,methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol,2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C., depending on the specificreactants, solvents, and other optional additives used. Such reactionsmay also be promoted by the addition of optional additives. Examples ofsuch additives include, but are not limited to, hydroxybenztriazole(HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB),4-dimethylaminopyridine (DMAP). Whether these additives are necessarydepends on the identity of the reactants, the solvent, and thetemperature, and such a choice is within the knowledge of one ofordinary skill in the art.

In general, the leaving group Y¹ in the compounds of formula (II) shouldbe such that it provides sufficient reactivity of the compounds offormula (II) with the compounds of formula (III). Compounds of formula(II) that contain such suitable leaving groups may be prepared, isolatedand/or purified, and subsequently reacted with the compounds of formula(III). Alternatively, compounds of formula (II) with suitable leavinggroups may be prepared and further reacted without isolation or furtherpurification with the compounds of formula (III) to afford compounds offormula (I). Among suitable leaving groups, Y¹, are halides, aromaticheterocycles, sulfonic acid esters, anhydrides, or groups derived fromthe reaction of compounds of formula (II) wherein Y¹ is hydroxy withreagents such as carbodiimides or carbodiimide species. Examples ofsuitable leaving groups include, but are not limited to, chloride,iodide, imidazole, —OC(O)alkyl, —OC(O)aryl, —OC(O)Oalkyl, —OC(O)Oaryl,—OS(O₂)alkyl, —OS(O₂)aryl, —OPO(Oaryl)₂, —OPO(Oalkyl)₂, and thosederived from the reaction of the compounds of formula (II) wherein Y¹ is—OH with carbodiimides. Other suitable leaving groups are known to thoseof ordinary skill in the art and may be found, for example, in Humphrey,J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243; ComprehensiveOrganic Synthesis; Trost, B. M., Ed.; Pergamon: New York, 1991; Vol. 6,pp 301-434; and Comprehensive Organic Transformations; Larock, R. C.;VCH: New York, 1989, Chapter 9.

Compounds of formula (II) where in Y¹ is a halogen can be prepared fromcompounds of formula (II) wherein Y¹ is hydroxy by reaction with asuitable agent. For example, the compounds of formula (II) wherein Y¹ ischloro may be prepared from compounds of formula (II) wherein Y¹ ishydroxy by reaction with agents such as thionyl chloride or oxalylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (III) or they may beformed in situ and reacted with the compounds of formula (III) withoutisolation or further purification. These reactions may be performed in asolvent that does not interfere with the desired transformation. Amongsuitable solvents are alkyl or aryl ethers, alkyl or aryl esters,aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or arylnitriles, alkyl or aryl ketones, aromatic hydrocarbons, orheteroaromatic hydrocarbons. For example, suitable solvents include, butare not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate,n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropylether, chlorobenzene, dimethyl formamide, dimethyl acetamide,propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethylether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

The present invention specifically contemplates that the compounds offormula (I-A) may be prepared by reacting compounds of formula (III)with compounds of formula (II), wherein R is hydrogen, an optionallysubstituted C₁₋₄ alkyl group, or a suitable protecting group, such as aC₁₋₆ alkylcarbonyl, C₆₋₁₀ arylcarbonyl, or heteroarylcarbonyl group. Forexample, as shown below, compound (2), wherein R³ is methylcarboxy, wastreated with thionyl chloride in a mixture of pyridine and acetonitrileand was then allowed to react with compound (3) to afford the desiredcompound (4), as shown below.

Alternatively, as shown below, compound (5) wherein R³ is hydrogen, wasallowed to react with compound (3) to afford the desired product,compound (6).

Whether R³ in the compounds of formula (II) is hydrogen, an optionallysubstituted C₁₋₄ alkyl group, or a suitable protecting group isdependent on the specific product compounds desired and/or the specificreaction conditions used. Such choices are within the knowledge of oneof ordinary skill in the art.

Compounds of formula (II) where in Y¹ is an aromatic heterocycle can beprepared from compounds of formula (II) wherein Y¹ is hydroxy byreaction with a suitable agent such as carbonyl diimidazole. Thesecompounds may be isolated and then further reacted with the compounds offormula (III) or they may be formed in situ and reacted with thecompounds of formula (III) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such knowledge is within the skill of oneof ordinary skill in the art.

Compounds of formula (II) wherein Y¹ is —OC(O)alkyl or —OC(O)aryl may beprepared from compounds of formula (II) wherein Y¹ is hydroxy byreaction with suitable reagents such acyl halides, acyl imidazoles, orcarboxylic acid under dehydrating conditions. Suitable reagents mayinclude, but are not limited to, acetyl chloride, acetyl iodide formedin situ from acetyl chloride and sodium iodide, acetyl imidazole, oracetic acid under dehydrating conditions. These reactions may beperformed in the presence of a suitable base such as sodium carbonate,sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodiumhydroxide, potassium hydroxide, a trialkylamine, triethylamine forexample, or a heteroaromatic base, pyridine for example. The resultingcompounds may be isolated and then further reacted with the compounds offormula (III) or they may be formed in situ and reacted with thecompounds of formula (III) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such choices are within the knowledge ofone of ordinary skill in the art.

Compounds of formula (II) wherein Y¹ is —OC(O)Oalkyl, —OC(O)Oaryl can beprepared from compounds of formula (II) wherein Y¹ is hydroxy byreaction with a suitable agents such as chloroformates of the formulaClC(O)Oalkyl or ClC(O)Oaryl. These reactions may be performed in thepresence of a suitable base such as sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, sodiumhydroxide, potassium hydroxide, a trialkylamine, triethylamine forexample, or a heteroaromatic base, pyridine for example. The resultingcompounds may be isolated and then further reacted with the compounds offormula (III) or they may be formed in situ and reacted with thecompounds of formula (III) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such choices are within the knowledge ofone of ordinary skill in the art.

Compounds of formula (II) wherein Y¹ is —OS(O₂)alkyl or —OS(O₂)aryl canbe prepared from compounds of formula (II) wherein Y¹ is hydroxy byreaction with a suitable agent such as an alkyl or aryl sulfonylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (III) or they may beformed in situ and reacted with the compounds of formula (III) withoutisolation or further purification. These reactions may be performed in asolvent that does not interfere with the desired transformation. Amongsuitable solvents are alkyl or aryl ethers, alkyl or aryl esters,aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or arylnitriles, alkyl or aryl ketones, aromatic hydrocarbons, orheteroaromatic hydrocarbons. For example, suitable solvents include, butare not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate,n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropylether, chlorobenzene, dimethyl formamide, dimethyl acetamide,propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethylether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Alternatively, compounds of formula (I) may be prepared by reaction ofcompounds of formula (II), wherein Y¹ is —OH, with compounds of formula(III) under dehydrating conditions, utilizing agents such ascarbodiimides or carbodiimide derived species. Such suitable agentsinclude, but are not limited to, dicyclohexylcarbodiimide,diisopropylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDC), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT),cyanuric chloride,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), carbonyldiimidazole (CDI),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(BOP), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrefluoroborate (TBTU), and3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). Thesereactions may be performed in the presence of optional additives.Suitable additives include, but are not limited to, hydroxybenztriazole(HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB), and4-dimethylaminopyridine (DMAP). Whether these additives are necessarydepends on the identity of the reactants, the solvent, and thetemperature, and such choices are within the knowledge of one ofordinary skill in the art. For example, as shown below, compound (5) wastreated with diisopropylcarbodiimide (DIC) in the presence of HOBt andin 2-methyltetrahydrofuran and was then allowed to react with compound(3) to afford the desired product.

Compounds of formula (II), wherein R³ is a suitable protecting group andY¹ and R¹ are as hereinbefore defined, may be prepared from compounds offormula (II) wherein R³ is hydrogen. The choice of a suitable protectinggroup is dependent upon the subject compound chosen and subsequentreaction conditions to which the compound of formula (II) will besubjected. Generally, R³ in the compounds of formula II can be chosenfrom alkyl or aryl esters, alkyl silanes, aryl silanes, alkylarylsilanes, carbonates, optionally substituted benzyl ethers, or othersubstituted ethers. Such protecting groups can be introduced into thecompounds of formula (II) wherein R³ is hydrogen using methods known tothose of ordinary skill in the art and as found in, for example, T.Greene and P. Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.),John Wiley & Sons, NY (1999). For example, as shown below, compound (2)was allowed to react with acetic anhydride in ethyl acetate andmethanesulfonic acid at about 70° C. to afford compound (5).

Compounds of formula (II), wherein Y¹ is hydroxy and R¹ and R³ are ashereinbefore defined, can be prepared by reaction of compounds offormula (IV), wherein Y¹ and R³ are as hereinbefore defined, withcompounds of formula (V), wherein R¹ is as hereinbefore defined and Y²is hydroxy or a suitable leaving group, as shown below.

In general, these reactions may be performed in a solvent that does notinterfere with the reaction, for example alkyl or aryl ethers, alkyl oraryl esters, aromatic and aliphatic hydrocarbons, non-competitivealcohols, halogenated solvents, alkyl or aryl nitriles, alkyl or arylketones, aromatic hydrocarbons, or heteroaromatic hydrocarbons. Forexample, suitable solvents include, but are not limited to, ethylacetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene,dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile,t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether,diphenyl ether, methylphenyl ether, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane,methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol,2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C., depending on the specificreactants, solvents, and other optional additives used. Such reactionsmay also be promoted by the addition of optional additives. Examples ofsuch additives include, but are not limited to, hydroxybenztriazole(HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB), and4-dimethylaminopyridine (DMAP). Whether these additives are necessarydepends on the identity of the reactants, the solvent, and thetemperature. Such choices are within the knowledge of one of ordinaryskill in the art.

In general, the leaving group Y² in the compounds of formula (V) shouldbe such that it provides sufficient reactivity with the amine in thecompounds of formula (IV). Compounds of formula (V) that contain suchsuitable leaving groups may be prepared, isolated and/or purified, andsubsequently reacted with the compounds of formula (IV). Alternatively,compounds of formula (V) with suitable leaving groups may be preparedand further reacted without isolation or further purification with thecompounds of formula (IV) to afford compounds of formula (II). Amongsuitable leaving groups in the compounds of formula (V) are halides,aromatic heterocycles, sulfonic acid esters, anhydrides, or groupsderived from the reaction of compounds of formula (V) wherein Y² ishydroxy with reagents such as carbodiimides or carbodiimide species.Examples of suitable leaving groups include, but are not limited to,chloride, iodide, imidazole, —OC(O)alkyl, —OC(O)aryl, —OC(O)Oalkyl,—OC(O)Oaryl, —OS(O₂)alkyl, —OS(O₂)aryl, —OPO(Oaryl)₂, OPO(Oalkyl)₂, andthose derived from the reaction of the compounds of formula V wherein Y²is —OH with carbodiimides. Other suitable leaving groups are known tothose of ordinary skill in the art and may be found, for example, inHumphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97, 2243;Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon: New York,1991; Vol. 6, pp 301-434; and Comprehensive Organic Transformations;Larock, R. C.; VCH: New York, 1989, Chapter 9.

Compounds of formula (V) where in Y² is a halogen can be prepared fromcompounds of formula (V) wherein Y² is hydroxy by reaction with asuitable agent. For example, the compounds of formula (V) wherein Y² ischloro may be prepared from compounds of formula (V) wherein Y² ishydroxy by reaction with agents such as thionyl chloride or oxalylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (IV) or they may be formedin situ and reacted with the compounds of formula (IV) without isolationor further purification. These reactions may be performed in a solventthat does not interfere with the desired transformation. Among suitablesolvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic andaliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles,alkyl or aryl ketones, aromatic hydrocarbons, or heteroaromatichydrocarbons. For example, suitable solvents include, but are notlimited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether,chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart. For example, as shown below, compound (7) was allowed to react withcompound (8) in a mixture of tetrahydrofuran and water, in the presenceof triethylamine, at room temperature to afford the desired compound(5).

Compounds of formula (IV), wherein Y¹ is hydroxy and R³ is as definedabove, are either commercially available or can be prepared by methodsknown to those of skill in the art.

For example, the compounds of formula (IV) can be prepared as shown inthe scheme below. In general, an N-protected amino acid derivative isreduced to an aldehyde using reducing agents that are suitable for sucha transformation. For example, suitable reducing agents are dialkylaluminum hydride agents, such as diisobutyl aluminum hydride forexample. Another method of preparing the compounds of formula (IV) is toreduce an appropriate carboxylic acid to an alcohol with a suitablereducing agent such as LiAlH₄ or BH₃ or NaBH₄ for example, followed byoxidation of the alcohol to the corresponding aldehyde with PCC, underSwern conditions or using pyr.SO₃/DMSO/NEt₃ for example Another methodof preparing the compounds of formula (IV) is to reduce an appropriatecarboxylic acid derivative, such as a Weinreb amide or an acylimidazole, using a suitable reducing agent such as LiAlH₄ or diisobutylaluminum hydride for example. Alternatively, the compounds of formula(IV) can be prepared by the preparation of an appropriate aldehyde byreduction of the corresponding acid chloride. Next, a compound is addedto the aldehyde that is the equivalent of adding a carboxylate CO₂anion. For example, cyanide can be added to the aldehyde to afford acyanohydrin that can then be hydrolyzed under either acidic or basicconditions to afford the desired compound, (d). Alternatively,nitromethane may be added to the aldehyde under basic conditions toafford an intermediate that is then converted into the desired compound.These compounds can be prepared according to the following procedures.In those compounds where Y³ is —CN, R. Pedrosa et al., TetrahedronAsymm. 2001, 12, 347. For those compounds in which Y³ is —CH₂NO₂, M.Shibasaki et al., Tetrahedron Lett. 1994, 35,6123.

Compounds of formula (V), wherein Y² is hydroxy and R¹ is ashereinbefore defined, are either commercially available or can beprepared by methods known to those of skill in the art. For example,such compounds can be prepared from the corresponding alcohols byoxidation with suitable reagents. Such oxidation agents include, but arenot limited to, KMnO₄, pyridinium dichromate (PDC), H₂Cr₂O₇ (Jone'sreagent), and 2,2,6,6-tetramethylpiperidinyl-2-oxyl (TEMPO)/NaClO₂.

Compounds of formula (III), wherein Z is S, O, SO, SO₂, CH₂, or CFH, andR², R^(2′), R⁴, R⁵, R⁶, and R⁷ are as hereinbefore defined, are eithercommercially available or can be prepared according to methods known tothose of skill in the art. For example, see Mimoto, T.; et. al. J. Med.Chem. 1999, 42, 1789; EP 0751145; and U.S. Pat. Nos. 5,644,028,5,932,550, 5,962,640, and 6,222,043, which are hereby incorporated byreference.

Alternatively, the compounds of formula (I-A), wherein R¹ is phenyloptionally substituted by at least one substituent independently chosenfrom C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy, C₆₋₁₀ arylcarbonyloxy,and heteroarylcarbonyloxy, and Z, R², R^(2′), R³, R⁴, R⁵, R⁶, and R⁷ areas hereinbefore defined, may be prepared by reaction of compounds offormula (VI),

wherein Z, R², R^(2′), R³, R⁴, R⁵, R⁶, and R⁷ are as hereinbeforedefined with compounds of formula (V), wherein R¹ and Y² are ashereinbefore defined.

In general, these reactions may be performed in a solvent that does notinterfere with the reaction, for example alkyl or aryl ethers, alkyl oraryl esters, aromatic and aliphatic hydrocarbons, non-competitivealcohols, halogenated solvents, alkyl or aryl nitriles, alkyl or arylketones, aromatic hydrocarbons, or heteroaromatic hydrocarbons. Forexample, suitable solvents include, but are not limited to, ethylacetate, isobutyl acetate, isopropyl acetate, n-butyl acetate, methylisobutyl ketone, dimethoxyethane, diisopropyl ether, chlorobenzene,dimethyl formamide, dimethyl acetamide, propionitrile, butyronitrile,t-amyl alcohol, acetic acid, diethyl ether, methyl-t-butyl ether,diphenyl ether, methylphenyl ether, tetrahydrofuran,2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane, heptane,methanol, ethanol, 1-propanol, 2-propanol, t-butanol, n-butanol,2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C., depending on the specificreactants, solvents, and other optional additives used. Such reactionsmay also be promoted by the addition of optional additives. Examples ofsuch additives include, but are not limited to, hydroxybenztriazole(HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB), and4-dimethylaminopyridine (DMAP).Whether these additives are necessarydepends on the identity of the reactants, the solvent, and thetemperature. Such choices are within the knowledge of one of ordinaryskill in the art.

In general, the leaving group Y² in the compounds of formula (V) shouldbe such that it provides sufficient reactivity with the amino group inthe compounds of formula (VI). Compounds of formula (V) that containsuch suitable leaving groups may be prepared, isolated and/or purified,and subsequently reacted with the compounds of formula (VI).Alternatively, compounds of formula (V) with suitable leaving groups maybe prepared and further reacted without isolation or furtherpurification with the compounds of formula (VI) to afford compounds offormula (I). Among suitable leaving groups in the compounds of formula(V) are halides, aromatic heterocycles, sulfonic acid esters,anhydrides, or groups derived from the reaction of compounds of formula(V) wherein Y² is hydroxy with reagents such as carbodiimides orcarbodiimide species. Examples of suitable leaving groups include, butare not limited to, chloride, iodide, imidazole, —OC(O)alkyl,—OC(O)aryl, —OC(O)Oalkyl, —OC(O)Oaryl, —OS(O₂)alkyl, —OS(O₂)aryl,—OPO(Oaryl)₂, —OPO(Oalkyl)₂, and those derived from the reaction of thecompounds of formula (V), wherein Y² is —OH, with carbodiimides.

Compounds of formula (V) where in Y² is a halogen can be prepared fromcompounds of formula (V) wherein Y² is hydroxy by reaction with asuitable agent. For example, the compounds of formula (V) wherein Y² ischloro may be prepared from compounds of formula (V) wherein Y² ishydroxy by reaction with agents such as thionyl chloride or oxalylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (VI) or they may be formedin situ and reacted with the compounds of formula (VI) without isolationor further purification. These reactions may be performed in a solventthat does not interfere with the desired transformation. Among suitablesolvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic andaliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles,alkyl or aryl ketones, aromatic hydrocarbons, or heteroaromatichydrocarbons. For example, suitable solvents include, but are notlimited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether,chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Compounds of formula (VI),

wherein Z, R², R^(2′), R³, R⁴, R⁵, R⁶, and R⁷ are as hereinbeforedefined, may be prepared from reaction of compounds of formula (VII),

wherein Pg¹ is a suitable nitrogen protecting group, Y⁴ is hydroxy or asuitable leaving group, and R³ is as hereinbefore defined, with acompound of formula (III), wherein Z, R², R^(2′), R⁴, R⁵, R⁶, and R⁷ areas hereinbefore defined, or a salt or solvate thereof

A suitable protecting group Pg¹ in the compounds of formula (VII) is onethat is stable to subsequent reaction conditions in which the compoundsof formula (VII) are allowed to react with the compounds of formula(III). Furthermore, such a protecting group should be chosen such thatit can be removed after the compounds of formula (VII) have been allowedto react with the compounds of formula (III) to afford an intermediatecompound that is subsequently deprotected to afford a compound offormula (VI). Suitable protecting groups include, but are not limitedto, carbamates such as t-butyloxycarbonyl and benzyloxycarbonyl, imidessuch as phthaloyl, or suitable benzyl groups. Such protecting groups canbe introduced into the compounds of formula (VII) and subsequentlyremoved to provide compounds of formula (VI) according to methods knownto those of ordinary skill in the art and as found in, for example, T.Greene and P. Wuts, Protective Groups in Organic Synthesis (3^(rd) ed.),John Wiley & Sons, NY (1999).

In general, the leaving group Y⁴ in the compounds of formula (VII)should be such that it provides sufficient reactivity with the aminogroup in the compounds of formula (III). Compounds of formula (VII) thatcontain such suitable leaving groups may be prepared, isolated and/orpurified, and subsequently reacted with the compounds of formula (III).Alternatively, compounds of formula (VII) with suitable leaving groupsmay be prepared and further reacted without isolation or furtherpurification with the compounds of formula (III) to afford compounds offormula (VI). Among suitable leaving groups in the compounds of formula(VII) are halides, aromatic heterocycles, sulfonic acid esters,anhydrides, or groups derived from the reaction of compounds of formula(VII) wherein Y⁴ is hydroxy with reagents such as carbodiimides orcarbodiimide species. Examples of suitable leaving groups include, butare not limited to, chloride, iodide, imidazole, —OC(O)alkyl,—OC(O)aryl, —OC(O)Oalkyl, —OC(O)Oaryl, —OS(O₂)alkyl, —OS(O₂)aryl,—OPO(Oaryl)₂, —OPO(Oalkyl)₂, and those derived from the reaction of thecompounds of formula (VII), wherein Y⁴ is —OH, with carbodiimides.

Compounds of formula (VII) where in Y⁴ is a halogen can be prepared fromcompounds of formula (VII) wherein Y⁴ is hydroxy by reaction with asuitable agent. For example, the compounds of formula (VII) wherein Y⁴is chloro may be prepared from compounds of formula (VII) wherein Y⁴ ishydroxy by reaction with agents such as thionyl chloride or oxalylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (III) or they may beformed in situ and reacted with the compounds of formula (III) withoutisolation or further purification. These reactions may be performed in asolvent that does not interfere with the desired transformation. Amongsuitable solvents are alkyl or aryl ethers, alkyl or aryl esters,aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or arylnitriles, alkyl or aryl ketones, aromatic hydrocarbons, orheteroaromatic hydrocarbons. For example, suitable solvents include, butare not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate,n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropylether, chlorobenzene, dimethyl formamide, dimethyl acetamide,propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethylether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Compounds of formula (VII) where in Y⁴ is an aromatic heterocycle can beprepared from compounds of formula (VII) wherein Y⁴ is hydroxy byreaction with a suitable agent such as carbonyl diimidazole. Thesecompounds may be isolated and then further reacted with the compounds offormula (III) or they may be formed in situ and reacted with thecompounds of formula (III) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such choices are within the skill of oneof ordinary skill in the art.

Compounds of formula (VII) wherein Y⁴ is —OC(O)alkyl or —OC(O)aryl maybe prepared from compounds of formula (VII) wherein Y⁴ is hydroxy byreaction with suitable reagents such acyl halides, acyl imidazoles, orcarboxylic acid under dehydrating conditions. Suitable reagents mayinclude, but are not limited to, pivaloyl chloride, acetyl chloride,acetyl iodide formed in situ from acetyl chloride and sodium iodide,acetyl imidazole, or acetic acid under dehydrating conditions. Thesereactions may be performed in the presence of a suitable base such assodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine,triethylamine for example, or a heteroaromatic base, pyridine forexample. The resulting compounds may be isolated and then furtherreacted with the compounds of formula (III) or they may be formed insitu and reacted with the compounds of formula (III) without isolationor further purification. These reactions may be performed in a solventthat does not interfere with the desired transformation. Among suitablesolvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic andaliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles,alkyl or aryl ketones, aromatic hydrocarbons, or heteroaromatichydrocarbons. For example, suitable solvents include, but are notlimited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether,chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Compounds of formula (VII) wherein Y⁴ is —OC(O)Oalkyl, —OC(O)Oaryl canbe prepared from compounds of formula (VII) wherein Y⁴ is hydroxy byreaction with a suitable agents such as chloroformates of the formulaCl—C(O)Oalkyl or Cl—C(O)Oaryl. These reactions may be performed in thepresence of a suitable base such as sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, sodiumhydroxide, potassium hydroxide, a trialkylamine, triethylamine forexample, or a heteroaromatic base, pyridine for example. The resultingcompounds may be isolated and then further reacted with the compounds offormula (III) or they may be formed in situ and reacted with thecompounds of formula (III) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such choices are within the knowledge ofone of ordinary skill in the art.

Compounds of formula (VII) wherein Y⁴ is —OS(O₂)alkyl or —OS(O₂)aryl canbe prepared from compounds of formula (VII) wherein Y⁴ is hydroxy byreaction with a suitable agent such as an alkyl or aryl sulfonylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (III) or they may beformed in situ and reacted with the compounds of formula (III) withoutisolation or further purification. These reactions may be performed in asolvent that does not interfere with the desired transformation. Amongsuitable solvents are alkyl or aryl ethers, alkyl or aryl esters,aromatic and aliphatic hydrocarbons, halogenated solvents, alkyl or arylnitriles, alkyl or aryl ketones, aromatic hydrocarbons, orheteroaromatic hydrocarbons. For example, suitable solvents include, butare not limited to, ethyl acetate, isobutyl acetate, isopropyl acetate,n-butyl acetate, methyl isobutyl ketone, dimethoxyethane, diisopropylether, chlorobenzene, dimethyl formamide, dimethyl acetamide,propionitrile, butyronitrile, t-amyl alcohol, acetic acid, diethylether, methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Alternatively, compounds of formula (VI) may be prepared by reaction ofcompounds of formula (VII), wherein Y⁴ is —OH, with compounds of formula(III) under dehydrating conditions using agents such as carbodiimides orcarbodiimide derived species. Suitable agents include, but are notlimited to, dicyclohexylcarbodiimide, diisopropylcarbodiimide,1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC),2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), cyanuric chloride,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), carbonyldiimidazole (CDI),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(BOP), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrefluoroborate (TBTU), and3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). Thesereactions may be performed in the presence of optional additives.Suitable additives include, but are not limited to, hydroxybenztriazole(HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB), and4-dimethylaminopyridine (DMAP). Whether these additives are necessarydepends on the identity of the reactants, the solvent, and thetemperature. Such choices are within the knowledge of one of ordinaryskill in the art.

Alternatively, the compounds of formula (I) may be prepared by reactionof a compound of formula (VIII),

wherein Y⁵ is hydroxy or a suitable leaving group, and Z, R¹, R³, R⁴,R⁵, R⁶, and R⁷ are as hereinbefore defined, with a compound of formula(IX),

wherein R² and R^(2′) are hereinbefore defined, or a salt or solvatethereof.

In general, the leaving group Y⁵ in the compounds of formula (VIII)should be such that it provides sufficient reactivity with the aminogroup in the compounds of formula (IX). Compounds of formula (VIII) thatcontain such suitable leaving groups may be prepared, isolated and/orpurified, and subsequently reacted with the compounds of formula (IX).Alternatively, compounds of formula (VIII) with suitable leaving groupsmay be prepared and further reacted without isolation or furtherpurification with the compounds of formula (IX) to afford compounds offormula (I-A). Among suitable leaving groups in the compounds of formula(VIII) are halides, aromatic heterocycles, sulfonic acid esters,anhydrides, or groups derived from the reaction of compounds of formula(VIII) wherein Y⁵ is hydroxy with reagents such as carbodiimides orcarbodiimide species. Examples of suitable leaving groups include, butare not limited to, chloride, iodide, imidazole, —OC(O)alkyl,—OC(O)aryl, —OC(O)Oalkyl, —OC(O)Oaryl, —OS(O₂)alkyl, —OS(O₂)aryl, andthose derived from the reaction of the compounds of formula (VIII),wherein Y⁵ is —OH, with carbodiimides.

Compounds of formula (VIII) where in Y⁵ is a halogen can be preparedfrom compounds of formula (VIII) wherein Y⁵ is hydroxy by reaction witha suitable agent. For example, the compounds of formula (VIII) whereinY⁵ is chloro may be prepared from compounds of formula (VIII) wherein Y⁵is hydroxy by reaction with agents such as thionyl chloride or oxalylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (IX) or they may be formedin situ and reacted with the compounds of formula (IX) without isolationor further purification. These reactions may be performed in a solventthat does not interfere with the desired transformation. Among suitablesolvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic andaliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles,alkyl or aryl ketones, aromatic hydrocarbons, or heteroaromatichydrocarbons. For example, suitable solvents include, but are notlimited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether,chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Compounds of formula (VIII) where in Y⁵ is an aromatic heterocycle canbe prepared from compounds of formula (VIII) wherein Y⁵ is hydroxy byreaction with a suitable agent such as carbonyl diimidazole. Thesecompounds may be isolated and then further reacted with the compounds offormula (IX) or they may be formed in situ and reacted with thecompounds of formula (IX) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such choices are within the knowledge ofone of ordinary skill in the art.

Compounds of formula (VIII) wherein Y⁵ is —OC(O)alkyl or —OC(O)aryl maybe prepared from compounds of formula (VIII) wherein Y⁵ is hydroxy byreaction with suitable reagents such acyl halides, acyl imidazoles, orcarboxylic acid under dehydrating conditions. Suitable reagents mayinclude, but are not limited to, pivaloyl chloride, acetyl chloride,acetyl iodide formed in situ from acetyl chloride and sodium iodide,acetyl imidazole, or acetic acid under dehydrating conditions. Thesereactions may be performed in the presence of a suitable base such assodium carbonate, sodium bicarbonate, potassium carbonate, potassiumbicarbonate, sodium hydroxide, potassium hydroxide, a trialkylamine,triethylamine for example, or a heteroaromatic base, pyridine forexample. The resulting compounds may be isolated and then furtherreacted with the compounds of formula (IX) or they may be formed in situand reacted with the compounds of formula (IX) without isolation orfurther purification. These reactions may be performed in a solvent thatdoes not interfere with the desired transformation. Among suitablesolvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic andaliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles,alkyl or aryl ketones, aromatic hydrocarbons, or heteroaromatichydrocarbons. For example, suitable solvents include, but are notlimited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether,chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Compounds of formula (VIII) wherein Y⁵ is —OC(O)Oalkyl, —OC(O)Oaryl canbe prepared from compounds of formula (VIII) wherein Y⁵ is hydroxy byreaction with a suitable agents such as chloroformates of the formulaCl—C(O)Oalkyl or Cl—C(O)Oaryl. These reactions may be performed in thepresence of a suitable base such as sodium carbonate, sodiumbicarbonate, potassium carbonate, potassium bicarbonate, sodiumhydroxide, potassium hydroxide, a trialkylamine, triethylamine forexample, or a heteroaromatic base, pyridine for example. The resultingcompounds may be isolated and then further reacted with the compounds offormula (IX) or they may be formed in situ and reacted with thecompounds of formula (IX) without isolation or further purification.These reactions may be performed in a solvent that does not interferewith the desired transformation. Among suitable solvents are alkyl oraryl ethers, alkyl or aryl esters, aromatic and aliphatic hydrocarbons,halogenated solvents, alkyl or aryl nitriles, alkyl or aryl ketones,aromatic hydrocarbons, or heteroaromatic hydrocarbons. For example,suitable solvents include, but are not limited to, ethyl acetate,isobutyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutylketone, dimethoxyethane, diisopropyl ether, chlorobenzene, dimethylformamide, dimethyl acetamide, propionitrile, butyronitrile, t-amylalcohol, acetic acid, diethyl ether, methyl-t-butyl ether, diphenylether, methylphenyl ether, tetrahydrofuran, 2-methyltetrahydrofuran,1,4-dioxane, pentane, hexane, heptane, methanol, ethanol, 1-propanol,2-propanol, t-butanol, n-butanol, 2-butanol, dichloromethane,chloroform, 1,2-dichloroethane, acetonitrile, benzonitrile, acetone,2-butanone, benzene, toluene, anisole, xylenes, and pyridine, or anymixture of the above solvents. Additionally, water may be used as aco-solvent in this transformation if necessary. Furthermore, suchreactions may be performed at temperatures from −20° C. to 100° C. Thespecific reaction conditions chosen will depend on the specific subjectcompound and reagents chosen. Such choices are within the knowledge ofone of ordinary skill in the art.

Compounds of formula (VIII) wherein Y⁵ is —OS(O₂)alkyl or —OS(O₂)arylcan be prepared from compounds of formula (VIII) wherein Y⁵ is hydroxyby reaction with a suitable agent such as an alkyl or aryl sulfonylchloride. These reactions may be performed in the presence of a suitablebase such as sodium carbonate, sodium bicarbonate, potassium carbonate,potassium bicarbonate, sodium hydroxide, potassium hydroxide, atrialkylamine, triethylamine for example, or a heteroaromatic base,pyridine for example. The resulting compounds may be isolated and thenfurther reacted with the compounds of formula (IX) or they may be formedin situ and reacted with the compounds of formula (IX) without isolationor further purification. These reactions may be performed in a solventthat does not interfere with the desired transformation. Among suitablesolvents are alkyl or aryl ethers, alkyl or aryl esters, aromatic andaliphatic hydrocarbons, halogenated solvents, alkyl or aryl nitriles,alkyl or aryl ketones, aromatic hydrocarbons, or heteroaromatichydrocarbons. For example, suitable solvents include, but are notlimited to, ethyl acetate, isobutyl acetate, isopropyl acetate, n-butylacetate, methyl isobutyl ketone, dimethoxyethane, diisopropyl ether,chlorobenzene, dimethyl formamide, dimethyl acetamide, propionitrile,butyronitrile, t-amyl alcohol, acetic acid, diethyl ether,methyl-t-butyl ether, diphenyl ether, methylphenyl ether,tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, pentane, hexane,heptane, methanol, ethanol, 1-propanol, 2-propanol, t-butanol,n-butanol, 2-butanol, dichloromethane, chloroform, 1,2-dichloroethane,acetonitrile, benzonitrile, acetone, 2-butanone, benzene, toluene,anisole, xylenes, and pyridine, or any mixture of the above solvents.Additionally, water may be used as a co-solvent in this transformationif necessary. Furthermore, such reactions may be performed attemperatures from −20° C. to 100° C. The specific reaction conditionschosen will depend on the specific subject compound and reagents chosen.Such choices are within the knowledge of one of ordinary skill in theart.

Alternatively, compounds of formula I may be prepared by reaction ofcompounds of formula (VIII), wherein Y⁵ is —OH, with compounds offormula (IX) under dehydrating conditions using agents such ascarbodiimides or carbodiimide derived species Such suitable agentsinclude, but are not limited to, dicyclohexylcarbodiimide,diisopropylcarbodiimide, 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (EDC), 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT),cyanuric chloride,4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride,O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), carbonyldiimidazole (CDI),benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate(BOP), 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ),2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate(HBTU), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluroniumtetrefluoroborate (TBTU), and3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT). Thesereactions may be performed in the presence of optional additives.Suitable additives include, but are not limited to, hydroxybenztriazole(HOBt), hydroxyazabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu),N-hydroxy-5-norbornene-endo-2,3-dicarboximide (HONB), and4-dimethylaminopyridine (DMAP). Whether these additives are necessarydepends on the identity of the reactants, the solvent, and thetemperature. Such choices are within the knowledge of one of ordinaryskill in the art.

Compounds of formula (IX) are either commercially available or can beprepared by methods described herein or methods known to those ofordinary skill in the art.

Preferably, the inventive compounds are prepared by the methods of thepresent invention, including the General Methods shown below. Whenstereochemistry is not specified in chemical structures, eitherstereocenter may be utilized. The following abbreviations also apply:Boc (tert-butoxycarbonyl), Ac (acetyl), Cbz (benzyloxycarbonyl), DMB(2,4-dimethoxybenzyl), TBS (tert-butyldimethylsilyl), TBDPS(tert-butyldiphenylsilyl), Ms (methanesulfonate), Ts (toluenesulfonate),Bn (benzyl), and Tr (triphenylmethyl)

Various starting materials and other reagents were purchased fromcommercial suppliers, such as Aldrich Chemical Company or LancasterSynthesis Ltd., and used without further purification, unless otherwiseindicated.

In the examples described below, unless otherwise indicated, alltemperatures in the following description are in degrees Celsius (° C.)and all parts and percentages are by weight, unless indicated otherwise.

The reactions set forth below were performed under a positive pressureof nitrogen, argon or with a drying tube, at ambient temperature (unlessotherwise stated), in anhydrous solvents. All commercial reagents andsolvents were used as received from their respective suppliers with thefollowing exceptions: Tetrahydrofuran (THF) was distilled from sodiumbenzophenone ketyl prior to use. Dichloromethane (CH₂Cl₂) was distilledfrom calcium hydride prior to use. Flash chromatography was performedusing silica gel 60 (Merck art. 9385). ¹H-NMR spectra were recorded on aBruker instrument operating at 300 MHz and ¹³CNMR spectra were recordedat 75 MHz. NMR spectra are obtained as DMSO-d₆ or CDCl₃ solutions(reported in ppm), using chloroform as the reference standard (7.25 ppmand 77.00 ppm) or DMSO-d₆ ((2.50 ppm and 39.52 ppm)). Other NMR solventswere used as needed. When peak multiplicities are reported, thefollowing abbreviations are used: s=singlet, d=doublet, t=triplet,m=multiplet, br=broadened, dd=doublet of doublets, dt=doublet oftriplets. Coupling constants, when given, are reported in Hertz.Alternatively, ¹H NMR spectra were recorded at 300 MHz utilizing aVarian UNITYplus 300 spectrometer. Chemical shifts are reported in ppm(δ) downfield relative to internal tetramethylsilane, and couplingconstants are given in Hertz. Infrared absorption spectra were recordedusing a Perkin-Elmer 1600 series FTIR spectrometer. Alternatively,infrared spectra were recorded on a Perkin-Elmer FT-IR Spectrometer asneat oils, as KBr pellets, or as CDCl₃ solutions, and when reported arein wave numbers (cm⁻¹). Elemental analyses were performed by AtlanticMicrolab, Inc., Norcross, Ga. Melting points are uncorrected.

Analytical thin-layer chromatography was performed on glass-backedsilica gel 60° F. 254 plates (Analtech (0.25 mm)) and eluted with theappropriate solvent ratios (v/v). The reactions were assayed byhigh-pressure liquid chromotagraphy (HPLC) or thin-layer chromatography(TLC) and terminated as judged by the consumption of starting material.The TLC plates were visualized by UV, phosphomolybdic acid stain, oriodine stain.

The mass spectra were obtained using LC/MS or APCI. All melting pointsare uncorrected.

All final products had greater than 95% purity (by HPLC at wavelengthsof 220 nm and 254 nm).

In the following examples and preparations, “Et” means ethyl, “Ac” meansacetyl, “Me” means methyl, “Ph” means phenyl, (PhO)₂POCl meanschlorodiphenylphosphate, “HCl” means hydrochloric acid, “EtOAc” meansethyl acetate, “Na₂CO₃” means sodium carbonate, “NaOH” means sodiumhydroxide, “NaCl” means sodium chloride, “NEt₃” means triethylamine,“THF” means tetrahydrofuran, “DIC” means diisopropylcarbodiimide, “HOBt”means hydroxy benzotriazole, “H₂O” means water, “NaHCO₃” means sodiumhydrogen carbonate, “K₂CO₃” means potassium carbonate, “MeOH” meansmethanol, “i-PrOAc” means isopropyl acetate, “MgSO₄” means magnesiumsulfate, “DMSO” means dimethylsulfoxide, “AcCl” means acetyl chloride,“CH₂Cl₂” means methylene chloride, “MTBE” means methyl t-butyl ether,“DMF” means dimethyl formamide, “SOC1₂” means thionyl chloride, “H₃PO₄”means phosphoric acid, “CH₃SO₃H” means methanesulfonic acid, “Ac₂O”means acetic anhydride, “CH₃CN” means acetonitrile, and “KOH” meanspotassium hydroxide.

All P2′ amine variants mentioned in General Methods A-E describedhereinbelow were either purchased and used directly or synthesized asfollows.Method A: Representative Procedure for Reduction of Ketones to Alcohols.

6,7-Dihydro-4-(5H)-benzofuranone (1) (1.00 g 7.34 mmol) was dissolved inmethanol (55 mL). The mixture was cooled to 0° C. and NaBH₄ (0.31 g,8.08 mmol) was added in portions. The reaction was stirred for 2 h at 0°C. at which time the methanol was evaporated. The residue was dissolvedin EtOAc and poured into NaHCO₃ (saturated aqueous) and extracted withEtOAc (3×10 mL). The combined organic extracts were washed with brine(10 mL), passed over a short plug of Na₂SO₄, and concentrated in vacuoto give 2 (1.01 g, 99%, as a mixture of isomers) as a pale yellow, thickoil, which was of sufficient quality to be advanced to the next stepwithout further purification. Rf (50% EtOAc/hexanes): 0.53.Method B: Representative Procedure for Reduction of Acids to Alcohols.

Tiglic acid (1) (20.0 g, 0.200 mol) was dissolved in ether (80 ml) andadded dropwise over 30 min to a suspension of LiAlH₄ (15.0 g, 0.417 mol)in ether (80 ml) at 0° C. and the reaction mixture was allowed to warmto room temperature. After 3 h the mixture was re-cooled to 0° C. andquenched slowly by the addition of H₂O (15 ml), 15% NaOH (15 ml) and H₂O(15 ml). The reaction mixture was filtered to remove the granularprecipitate and washed thoroughly with ether. The filtrate was washedsuccessively with 1N HCl, NaHCO₃ (saturated aqueous), and brine. Thecombined organic layers were dried over MgSO₄ and concentrated in vacuoto give (E)-2-methyl-but-2-en-1-ol (2) as a clear oil (12.8 g, 74%).Method C: Representative Procedure for Alkylation of Phenols Alcohols.

3-Hydroxybenzylalcohol (1) (0.500 g 4.03 mmol) was dissolved in DMF (2mL) at ambient temperature. Ethyl bromide (0.900 mL, 12.1 mmol) andfinely crushed K₂CO₃ (2.78 g, 20.1 mmol) were added and the reactionmixture was stirred for 5 h. The DMF was then removed in vacuo and theresidue was partitioned between EtOAc and H₂0, and extracted with EtOAc(3×10 mL). The organic layers were washed with brine (10 mL) and passedover a short plug of Na₂SO₄. The solvents were removed in vacuo to givealcohol 2 (0.55 g, 90%) as a pale yellow, thick oil, which was ofsufficient quality to be advanced to the next step without furtherpurification. Rf (40% EtOAC/hexanes): 0.69.Method D: Representative Procedure for Conversion of Alcohols to Amines.

3-Ethoxy-phenyl-methanol (1) (1.23 g 8.08 mmol) was dissolved in CH₂Cl₂(10 mL) at ambient temperature and diphenylphosphoryl azide (2.67 g,9.70 mmol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (1.45 mL, 9.70 mmol)were added. The mixture was stirred for 5 h at which time the CH₂Cl₂ wasremoved in vacuo and the crude residue was partitioned between EtOAc andH₂O and extracted with EtOAc (3×10 mL). The combined organic layers werewashed with brine (10 mL), passed over a short plug of Na₂SO₄, andconcentrated in vacuo to give a yellow oil that was loaded directly ontoa flash silica gel column and was quickly eluted with 10% EtOAc/hexanes.The solvents were removed in vacuo to give azide 2 (1.43 g, 84%) as acolorless oil. Rf (30% EtOAc/hexanes): 0.79.

1-Azidomethyl-3-ethoxy-benzene (2) (1.19 g 6.71 mmol) was dissolved inMeOH (15 mL) and palladium 10% on activated carbon, wet (20% in weight)was added. The reaction was hydrogenated for 30 min at 40 PSI in a ParrHydrogenator. The black suspension was then filtered through compactedcelite and the methanol was removed in vacuo to give amine 3 (0.88 g,88%) as a pale yellow, thick oil, which was of sufficient quality to beadvanced to the coupling reactions without further purification.Method E: Representative Procedure for Conversion of Alcohols toBromides.

Cis-2-penten-1-ol (1) (1.00 g, 11.6 mmol) and carbon tetrabromide (3.85g, 13.9 mmol) were dissolved in CH₂Cl₂ (75 mL). The mixture was cooledto 0° C. and triphenylphosphine (3.65 mL, 13.9 mmol) dissolved in CH₂Cl₂(50 mL) was added dropwise. The mixture was allowed to warm to roomtemperature and was stirred overnight. The CH₂Cl₂ was removed in vacuoand the crude residue was loaded directly onto a flash silica gel columnand eluted quickly with 20% EtOAc/hexanes. The solvents were removed invacuo to give bromide 2 (1.53 g, 88%) as a colorless volatile oil. Rf(30% EtOAC/hexanes): 0.89.Method F: Representative Procedure for Conversion of Bromides to Amines.

A mixture of bromide 1 (3.00 g, 20.1 mmol),di-tert-butyl-iminodicarboxylate (4.8 g, 22 mmol), and K₂CO₃ (3.10 g,80.4 mmol) in DMF (30 mL) was stirred at ambient temperature overnight.The mixture was partitioned between 1N HCl and EtOAc. The organic layerwas washed with H₂O and brine, then dried over NaSO₄. Concentration invacuo affored a yellow oil which upon purification by flash columnchromatography (hexanes to 5% EtOAc/Hexane gradient) yielded protectedamine 2 as a clear oil (2.0 g, 35%).

A mixture of the diBOC amine 2 (2.0 g, 7.0 mmol), trifluoroacetic acid(2.7 ml, 35 mmol) and CH₂Cl₂ (40 ml) was stirred at ambient temperatureovernight. The reaction mixture was concentrated in vacuo to give theTFA salt of (E)-2-methyl-but-2-enylamine (3).Method G: Representative Procedure for Reduction of Aromatic NitroGroups by Hydrogenation.

Compound 1 (2.04, 5.79 mmol) was dissolved in EtOAc (20 mL) andpalladium 10% on activated carbon, wet (20% in weight) was added. Thereaction was hydrogenated for 4 h at 45 PSI in a Parr Hydrogenator. Theblack suspension was then filtered through compacted celite and themethanol was removed in vacuo to give aniline 2 (1.65 g, 88%) as a paleyellow, thick oil, which was of sufficient quality to be advanced to theacetylation reaction without further purification.Method H: Representative Procedure for Acetylation of Anilines.

Aniline 1 (1.65 g, 5.12 mmol) was dissolved in CH₂Cl₂ (25 mL) at ambienttemperature. Acetyl chloride (0.48 g, 6.14 mmol) andN,N-Diisopropylethylamine (0.79 g, 6.14 mmol) were added, and thereaction was stirred overnight. The CH₂Cl₂ was removed in vacuo and thecrude residue was partitioned between EtOAc and 5% KHSO₄ and extractedwith EtOAc (3×10 mL). The combined organic extracts were washed withNaHCO₃ (saturated aqueous, 10 mL), brine (10 mL), and dried over Na₂SO₄.The solvents were removed in vacuo to give an orange oil which was ofsufficient quality to be advanced to the next step without furtherpurification. Rf (50% EtOAC/hexanes): 0.42.Method I: Representative Procedure for Reduction of Aldehydes to Amines.

Hydroxyl amine hydrochloride (758 mg, 10.7 mmol) and pyridine (2.16 mL)was added to a solution of 2,2-difluoro-5-formyl benzodioxole (1) (2.00g, 10.7 mmol) in MeOH (10 mL). After 18 hours the MeOH was removed invacuo. The reaction mixture was diluted with EtOAc and was washedsequentially with H₂O, 10% w/v CuSO₄, and brine and then dried overMgSO₄. The solution was concentrated in vacuo. The hydroxy imine waspurified by column chromatography using 20% EtOAc/Hexanes to give 1.37 g(64% yield) of a white solid. Imine was then subjected to LAH reductionas described above to provide amine 3.

The following amines were synthesized for the corresponding examplenumbers:

EXAMPLE A26

Amine was generated by alkylation of 3-hydroxybenzyl alcohol with ethylbromide as describe in method C above followed by conversion of thealcohol to the amine as described in method D above provided desiredamine.

EXAMPLE A43

Amine was generated as described above for Example A43 usingpropylbromide as the alkylating agent.

EXAMPLE A33

Amine was generated from displacement of bromide in 3-nitrobenzylbromidewith di BOC amine as described in method F above. Reduction of the nitromoiety to the aniline (method G above) followed by acetylation (method Habove) and BOC removal (method F above) provided desired amine.

EXAMPLE A36, EXAMPLE A37 and EXAMPLE A40

Amines were generated from conversion of the corresponding primaryalcohols as described in method E above. Displacement of the bromidewith di BOC amine and deprotection with TFA (method F above) providedthe desired amines.

EXAMPLE A39

Amine was generated from 3-dimethylaminobenzyl alcohol as described inmethod D above.

EXAMPLE A34

Amine was generated by reduction of the corresponding methyl ester tothe primary alcohol (Wipf, J. Org. Chem. 1994, 59, 4875-86.). Conversionto the bromide (method E above) followed by displacement with diBOCamine and deprotection (method F above) provided desired amine.

EXAMPLE A35

Amine was generated from the corresponding carboxylic acid. Reduction ofthe acid as described in method B above followed by bromide displacementas described in method E above gave the primary bromide. Conversion ofthe bromide to the primary amine followed the procedure described inmethod F above.

EXAMPLE A42

Amine was generated from 3-benzyloxybenzyl alcohol. Conversion to theazide and reduction of both the azide and benzyl protecting group wereaccomplished using method D as described above with longer hydrogenationtime.

EXAMPLE A44

Amine was generated by LiAlH₄ reduction of 2-cyanophenol (Ludeman, S.M., et. al. J. Med. Chem. 1975, 18, 1252-3.).

EXAMPLE A50

Amine was generated from the condensation of o-tolualdehyde with2-aminoethanol followed by reduction with sodium borohydride(Tetrahedron Assym. 1997, 8, 2367-74.).

EXAMPLE A48

Amine was generated from the corresponding aldehyde by the reductiveamination procedure described in method I above.

EXAMPLE A7

Amine was generated by a reductive amination with the correspondingaldehyde (Arch. Pharm. 1987, 320, 647-54.).

EXAMPLE A49

Amine was generated on the thiazolidine core as follows:

Diphenylchlorophosphate (1.0 ml, 4.2 mmol) followed by triethylamine(0.59 ml, 4.2 mmol) were added to a cooled 0° C. solution of BOC-DMTA 1(1.0 g, 3.8 mmol) in EtOAc (10 ml). The mixture was stirred for 1 h andat which time triethylamine (0.59 ml, 4.2 mmol) and ethanolamine (0.25ml, 4.2 mmol) were added. The reaction was left to stir overnight atambient temperature and then partitioned between 1N HCl and EtOAc. Theorganic layer was washed with NaHCO₃(saturated aqueous) and brine. Theorganic layer was dried over Na₂SO₄ and concentrated in vacuo to a paleyellow oil 2. The oil was stirred with thionyl chloride (2 ml) for 45min at room temperature. The mixture was concentrated in vacuo and theresidual oil was partitioned between 1N NaOH and EtOAc. The organiclayer was extracted with 1N HCl (2×20 ml). The combined aqueous layerswere made basic with 1N NaOH and then extracted with EtOAc (3×60 ml).The organic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give (R)-5,5-Dimethyl-thiazolidine-4-carboxylicacid (2-chloro-ethyl)-amide 3 as a clear oil (0.39 g, 55%).

The following amines were prepared as described:

The above amines were prepared according to Carlsen, H. J., J.Heterocycle Chem. 1997, 34, 797-806.

EXAMPLE A41

The above amine was prepared according to O'Brien, P. M., J. Med. Chem.1994, 37, 1810-1822.

The above amine was prepared according to Weinheim, G. Arch. Pharm.1987, 320, 647-654.

The synthesis of compounds with the general structure 5 is as follows.The boc-protected thiazolidine carboxylic acid 1 is coupled to therequisite amines 2 to yield amino amides 3 using a two step process. Theprocess includes treatment of 1 with 2 in the presence of eitherdiphenylchlorophosphate or HATU, followed by exposure to methanesulfonic acid. Final compounds 5 are obtained by a DCC-mediated couplingof 3 and 4 followed by deprotection of the P2 phenol. Final compoundswere purified either by flash chromatography or preparative HPLC.

An alternative approach to the general structure 5 is as follows. Thethiazolidine ester 6 is coupled to acid 7 under carbodiimide reactionconditions, resulting in product 8 which is converted to acid 9 by mildbase hydrolysis. Acid 9 is combined with various amines, usingdiphenylphosphoryl azide, followed by cleavage of the P2 acetate toyield final compounds 5. The products were purified by either flashchromatography or preparative HPLC.

EXAMPLE A13-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (1,2,3,4-tetrahydro-naphthalen-1-yl)-amide

The title compound was prepared as follows.(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1(0.3 g, 1. 15 mmol) was dissolved in EtOAc (3 mL) and cooled to 0° C.Diphenyl chlorophosphate (0.26 mL, 1.26 mmol) was added followed by TEA(0.18 mL, 1.26 mmol). The reaction was stirred at 0° C. for 1 h, andtreated with (S)-1,2,3,4-Tetrahydro-1-naphthylamine (0.19 g, 1.26 mmol).The reaction mixture was stirred at room temperature overnight, thenpartitioned between 1N HCl (5 mL) and EtOAc (10 mL). The organic layerwas washed with saturated NaHCO₃, brine, dried over Na₂SO₄ andconcentrated to a light yellow oil. The resulting crude oil wasdissolved in EtOAc (5 mL) and the cooled to 0° C. Methanesulfonic acid(0.36 mL, 5.32 mmol) was added and the solution was stirred at 0° C. for15 minutes, then at room temperature for 1 h. The mixture was re-cooledto 0° C. and quenched with 5% Na₂CO₃ (5 mL) then extracted with EtOAc(10 mL). The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give 3a as a yellow oil. The yellow oil 3a(0.34 g, 1.15 mmol) was dissolved in EtOAc (12 mL). AMB-AHPBA 4 (0.40 g,1.09 mmol) was added followed by HOBt (0. 15 g, 1.09 mmol). The mixturewas stirred at room temperature 1 h, then cooled to 0° C. DCC (0.24 g,1.15 mmol) was slowly added as solution in EtOAc (6 mL). The mixture waswarmed to room temperature and stirred overnight. The mixture wasfiltered and the filtrate was washed with 1N HCl (10 mL), saturatedNaHCO₃ (10 mL), brine (10 mL), dried over Na₂SO₄ and concentrated togive a crude white solid (contaminated with DCU). The DCU was removed byflash chromatography (30% to 50% EtOAc in hexanes) to provide a whitesolid, which was dissolved in MeOH (2 mL) and treated with 4N HCl in1,4-dioxane (0.26 mL, 1.1 mmol). The reaction was stirred at roomtemperature overnight then partitioned between 1N HCl (10 mL) and EtOAc(10 mL). The organic layer was washed with saturated NaHCO₃, dried overNa₂SO₄ and concentrated to a residue which was purified by flashchromatography (60% EtOAc in hexanes) to provide the title compound as awhite solid: mp=125-126° C.; IR (cm⁻¹) 3320, 2932, 1704, 1644, 1530,1454, 1361, 1284; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.28 (d, J=8.6, 1H),8.21 (d, J=8.8, 1H), 7.35-6.91 (m, 10H), 6.76 (d, J=8.0, 1H), 6.54 (d,J=7.5, 1H), 5.34 (d, J=6.0, 1H), 5.13 (d, J=9.0, 1H), 5.02 (d, J=9.0,1H), 4.60-4.30 (m, 4H), 2.81-2.68 (m, 4H), 1.81 (s, 3H), 1.78-1.60 (m,4H), 1.48 (s, 3H), 1.45 (s, 3 H); Anal. Calcd for C₃₄H₃₉N₃O₅S.1.5 H₂O:C, 64.95; H, 6.73; N, 6.68. Found: C, 64.88; H, 6.31; N, 6.18.

EXAMPLE A2(R)-3-((2S,3R)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-methoxy-benzylamide

White solid: mp 108-110° C.; IR (neat, cm⁻¹) 3310, 2965, 1644, 1586,1531, 1455, 1359, 1284; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.40 (t, J=6.0,1H), 8.09 (d, J=8.1, 1H), 7.31-6.52 (m, 12H), 5.49 (d, J=6.0, 1H), 5.12(d, J=9.3, 1H), 5.00 (d, J=9.3, 1H), 4.44-4.35 (m, 3H), 4.42 (s, 1H),4.09 (dd, J=15.0, 6.0, 1H), 3.69 (s, 3H), 2.87-2.67 (m, 2H), 1.82 (s,3H), 1.49 (s, 3H), 1.34 (s, 3 H); Anal. Calcd for C₃₂H₃₇N₃O₆S.0.75 H₂O:C, 63.50; H, 6.41; N, 6.94. Found: C, 63.60; H, 6.23; N, 6.80.

The following examples were prepared by the specific method outlinedabove using the requisite amine 2.

EXAMPLE A3(R)-3-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methoxy-benzylamide

White solid: mp=123-125° C.; IR (cm⁻¹) 3318, 2965, 1644, 1525, 1495,1464, 1286, 1246, 1120, 1030; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.26 (t,J=5.9, 1H), 8.14 (d, J=8.0, 1H), 7.39-7.13 (m, 6H), 6.95-6.76 (m, 5H),6.53 (d, J=7.5, 1H), 5.49 (d, J=6.0, 1H), 5.13 (d, J=9.0, 1H), 5.01 (d,J=9.0, 1H), 4.47 (s, 1H), 4.41-4.16 (m, 4H), 3.78 (s, 3H), 2.90-2.62 (m,2H), 1.81 (s, 3H), 1.49 (s, 3H). 1.32 (s, 3H); Anal. Calcd forC₃₂H₃₇N₃O₆S.0.75 H₂O: C, 63.50; H, 6.41; N, 6.94. Found: C, 63.68; H,6.20; N, 6.54.

EXAMPLE A43-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-trifluoromethyl-benzylamide

White solid: mp=108-110° C.; IR (cm⁻¹) 3308, 3065, 1646, 1540, 1456,1362, 1329, 1284, 1165, 1125, 1074; ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H),8.56 (t, J=6.0, 1H), 8.12 (d, J=8.2, 1H), 7.65 (s, 1H), 7.60-7.47 (m,3H), 7.28-7.13 (m, 5H), 6.96-6.92 (m, 1H), 6.77 (d, J=8.0, 1H), 6.53 (d,J=7.5, 1H), 5.45 (d, J=6.0, 1H), 5.14 (d, J=9.2, 1H), 5.00 (d, J=9.2,1H), 4.53-4.41 (m, 4H), 4.22 (dd, J=16.0, 6.0, 1H), 2.86-2.66 (m, 2H),1.81 (s, 3H), 1.49 (s, 3H), 1.31 (s, 3 H); Anal. Calcd forC₃₂H₃₄F₃N₃O₅S: C, 61.04; H, 5.44; N, 6.67. Found: C, 61.03; H, 5.56; N,6.51.

EXAMPLE A53-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methyanoyl]amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxlicacid fluoro trifluoromethyl-benzylamide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.69 (t, J=5.6, 1H), 8.12-6.56 (m,11H), 5.50 (d, J=6.0, 1H), 5.22 (d, J=9.3, 1H), 5.06 (d, J=9.3, 1H),4.60-4.36 (m, 5H), 4.50 (s, 1H), 2.89-2.67 (m, 2H), 1.83 (s, 3H), 1.55(s, 3H), 1.39 (s, 3H); Anal. Calcd for C₃₂H₃₃N₃O₅SF₄: C, 59.34; H, 5.14;N, 6.49; S, 4.95. Found: C, 59.06; H, 5.31; N, 6.22; S, 4.66.

EXAMPLE A6(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-methoxy-benzylamide

IR (neat cm⁻¹) 3335, 2920, 1641, 1516, 1463, 1374, 1285, 1249, 1172,1118; ¹H NMR (DMSO-_(d6)) δ 9.38 (s, 1H), 8.37 (t, J=5.5, 1H), 8.12 (d,J=8.2, 1H), 7.33-7.13 (m, 7H), 6.94 (t, J=7.7, 1H), 6.84-6.79 (m, 3H),6.54 (d, J=7.0, 1H), 5.48 (d, J=6.6, 1H), 5.12 (d, J=9.2, 1H), 5.00 (d,J=9.2, 1H), 4.49-4.42 (m, 3H), 4.32 (dd, J=6.2, 14.8, 6., 1H), 4.09 (dd,J=14.8, 5.3, 1H), 3.67 (s, 3H), 2.87-2.68 (m, 2H), 1.82 (s, 3H), 1.48(s, 3H), 1.32 (s, 3H); HRMS (ESI) m/z calcd for C₃₂H₃₇N₃O₆SNa (M+Na)⁺614.2301, found 614.2305; Anal. Calcd for C₃₂H₃₇N₃O₆S.0.75 H₂O: C,63.50; H, 6.41; N, 6.94. Found: C, 63.65; H, 6.43; N, 6.74.

EXAMPLE A73-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid methyl-(2-methyl-benzyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.44 (t, J=7.98, 1 H), 8.13-8.07 (m,2H), 7.34-7.13 (m, 9H), 6.93 (t, J=7.9, 1H), 6.78 (d, J=7.7, 1H), 6.53(d, J=7.1, 1H), 5.58 (d, J=6.8, 1H), 5.45 (d, J=7.0, 1H), 5.12 (ddJ=7.88.2 1H), 4.51-4.31(m, 6H), 2.86-2.67 (m, 2H), 2.19 (s, 3H), 1.81 (s,3H), 1.51 (s, 3H), 1.34 (s, 3H); Anal. Calcd for C₃₃H₃₉N₃O₅S.0.37 H₂O:C, 66.45; H, 6.72; N, 7.15. Found: C, 66.34; H, 7.28; N, 7.45.

EXAMPLE A83-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid methyl-(3-methyl-thiophen-2-ylmethyl)-amide

IR (neat or KBr cm⁻¹) 3150, 3000, 2942, 2187, 1712, 1600, 1567, 1505; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.44 (t, J=7.98, 1 H), 8.13-8.07 (m, 2H),7.34-7.13 (m, 5H), 6.93 (t, J=7.9, 1H), 6.78 (d, J=7.7, 1H), 6.53 (d,J=7.1, 1H), 5.45 (d, J=7.0, 1H), 5.12 (dd, J=7.8, 8.2 1H), 4.51-4.31(m,4H), 2.86-2.67 (m, 2H), 2.19 (s, 3H), 1.81 (s, 3H), 1.51 (s, 3H), 1.34(s, 3H); Anal. Calcd for C₃₀H₃₅N₃O₅S₂: calculated C, 61.94 H, 6.06 N,7.22. Found C, 62.38 H, 6.23, N, 7.17.

EXAMPLE A9(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-trifluoromethyl-benzylamide

IR (neat cm⁻¹) 3343, 2931, 1543, 1530, 1454, 1326, 1122; ¹H NMR(DMSO-d₆) δ 9.38 (s, 1H), 8.57 (t, J=5.0, 1H), 8.15 (d, J=8.4, 1H), 7.59(d, J=8.2, 2H), 7.50 (d, J=8.2, 2H), 7.28-7.13 (m, 5H), 6.93 (t, J=7.5,1H), 6.77 (d, J=7.7, 1H), 6.54 (d, J=7.3, 1H), 5.50 (s br, 1H), 5.15 (d,J=9.2, 1H), 5.02 (d, J=9.2, 1H), 4.47-4.21 (m, 5H), 2.85-2.67 (m, 2H),1.81 (s, 3H), 1.51 (s, 3H), 1.34 (s, 3H); ); HRMS (ESI) m/z calcd forC₃₂H₃₄F₃N₃O₅SNa (M+Na)⁺ 652.2063, found 652.2044; Anal. Calcd forC₃₂H34F₃N₃O₅S.0.25 H₂O: C, 60.60; H, 5.48; N, 6.63. Found: C, 60.50; H,5.29; N, 6.48.

EXAMPLE A10(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino-}4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-oxo-2-phenyl-ethyl)-amide

¹H NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.36 (t, J=4.8, 1H), 8.15 (d, J=8.1,1H), 7.98 (d, J=7.4, 1H), 7.65 (m, 1H), 7.52 (m, 2H), 7.32-7.11 (m, 6H),6.93 (t, J=7.9, 1H), 6.76 (d, J=7.9, 1H), 6.54 (d, J=7.5, 1H), 5.42 (d,J=6.4, 1H), 5.08 (d, J=9.3, 1H), 5.02 (d, J=9.0, 1H), 4.78-4.30 (m, 5H),2.84-2.66 (m, 2H), 1.81 (s, 3H), 1.57 (s, 3H), 1.45 (s, 3H); HRMS (ESI)m/z calcd for C₃₂H₃₅N₃O₆SNa (M+Na)⁺ 612.2139, found 612.2141.

EXAMPLE A113-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl-amino}-4-phenyl-butanoyl-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-fluoro-4-trifluoromethyl-benzylamide

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.62 (t, J=5.9, 1H), 8.09-6.54 (m,11H), 5.45 (s br, 1H), 5.18 (d, J=9.2, 1H), 5.03 (d, J=9.2, 1H),4.55-4.00 (m, 5H), 4.45 (s, 1H), 2.86-2.49 (m, 2H), 1.82 (s, 3H), 1.53(s, 3H), 1.36 (s, 3H); Anal. Calcd for C₃₂H₃₃N₃O₅SF₄: C, 59.34; H, 5.14;N, 6.49; S,4.95. Found: C, 59.14; H, 5.29; N, 6.21; S, 4.67.

EXAMPLE A123-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methyanoyl-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid -2-trifluoromethyl-4-fluoro-benzylamide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.65 (t, J=5.9, 1H), 8.12-6.54 (m,11H), 5.45 (d, J=6.9, 1H), 5.18 (d, J=9.2, 1H), 5.05 (d, J=9.2, 1H),4.59-4.34 (m, 5H), 4.50 (s, 1H), 2.85-2.67 (m, 2H), 1.82 (s, 3H), 1.53(s, 3H), 1.37 (s, 3H); Anal. Calcd for C₃₂H₃₃N₃O₅SF₄: C, 59.34; H, 5.14;N, 6.49; S, 4.95. Found: C, 59.26; H, 5.35; N, 6.23; S, 4.69.

EXAMPLE A133-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-methanesulfonyl-benzamide

¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.37 (t, J=5.5, 1H,), 8.12 (d, 1H,J=8.2, 1H,), 7.33-7.13 (m, 7H), 6.94 (t, 1H, J=7.7, 1H,), 6.84-6.79 (m,3H), 6.54 (d, 1H, J=7.3, 1H), 5.48 (d, J=6.6, 1H), 5.12 (d, J=9.2, 1H,),5.00 (d, 1H, J=9.2, 1H), 4.49-4.42 (m, 3H), 4.32 (dd, J=14.8, 6.2, 1H,),4.09 (dd, 1H, J=14.8, 5.3, 1H), 3.47 (s, 3H), 2.87-2.68 (m, 2H), 1.82(s, 3H), 1.48 (s, 3H), 1.32 (s, 3 H); Anal. Calcd for C₃₂H₃₇N₃O₇S₂: C,60.07; H, 5.83; N, 6.57. Found C, 60.25; H, 6.13; N, 6.74.

EXAMPLE A14(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

IR (neat cm⁻¹) 3342, 2966, 1637, 1531, 1460, 1366, 1284, 1108; ¹H NMR(DMSO-d₆) δ 9.36 (s, 1H), 8.13-8.07 (m, 2H), 7.34-7.13 (m, 5H), 6.93 (t,J=7.9, 1H), 6.78 (d, J=7.7, 1H), 6.53 (d, J=7.0, 1H), 5.82-5.70 (m. 1H),5.46 (d, J=6.6, 1H), 5.23-4.97 (m, 4H), 4.40 (m, 3H), 3.81-3.59 (m, 2H),2.86-2.67 (m, 2H), 1.81 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI)m/z calcd for C₂₇H₃₃N₃O₅S Na (M+Na)⁺ 534.2039, found 534.2062; Anal.Calcd for C₂₇H₃₃N₃O₅S: C, 63.38; H, 6.50; N, 8.21. Found: C, 63.68; H,6.57; N, 8.29.

EXAMPLE A15(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-dimethylamino-benzylamide

IR (neat cm⁻¹) 3331, 2931, 1643, 1519, 1455, 1349, 1284; ¹H NMR(DMSO-d₆) δ 9.37 (s, 1H), 8.26 (m, 1H), 8.12 (d, J=7.1, 1H), 7.38-6.92(m, 8H), 6.78 (t, J=7.9, 1H), 6.60 (d, J=8.6, 1H), 6.55 (d, J=7.3, 1H),6.42 (d, J=8.2, 1H), 5.46 (d, J=6.0, 1H), 5.11 (d, J=9.3, 1H), 5.00 (d,J=9.3, 1H), 4.45 (m, 3H), 4.25 (m, 1H), 4.03 (m, 1H), 2.80 (s, 3H),2.87-2.73 (m, 2H), 1.82 (s, 3H), 1.48 (s, 3H), 1.32 (s, 3 H); HRMS (ESI)m/z calcd for C₃₃H₄₀N₄O₅SNa (M+Na)⁺ 627.2612, found 627.2607.

EXAMPLE A16(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-amino-benzylamide

Pale yellow solid: mp=107-109° C.; IR (cm⁻¹) 3378, 2919, 1631, 1518,1453, 1382, 1281, 1121; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.21 (t, J=6.0,1H), 7.40-7.10 (m, 6H), 8.12 (d, J=8.1, 1H), 6.92 (d, J=8.4, 2H), 6.77(d, J=7.2, 1H), 6.54 (d, J=7.2, 1H), 6.44 (d, J=8.4, 2H), 5.44 (d,J=6.0, 1H), 5.10 (d, J=9.2, 1H), 4.99 (d, J=9.2, 1H), 4.90 (s, 2H),4.50-4.32 (m, 3H), 4.22-3.93 (m, 2H), 2.90-2.60 (m, 2H), 1.81 (s, 3H),1.47 (s, 3H), 1.31 (s, 3 H); Anal. Calcd for C₃₁H₃₆N₄O₅S.0.25 H₂O: C,64.06; H, 6.33; N, 9.64. Found: C, 64.17; H, 6.38; N, 9.60.

EXAMPLE A173-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid prop-2-ynylamide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.38 (t, J=5.5, 1H), 8.08(d, J=8.3,1H), 7.35-6.53 (m, 8H), 5.46 (d, J=6.6, 1H), 5.10 (d, J=9.2, 1H), 5.02(d, J=9.2, 1H), 4.44-4.40 (m, 1H), 4.40 (s, 1H), 3.85 (m, 3H), 3.08 (t,J=2.5, 1H), 2.88-2.68 (m, 2H), 1.82 (s, 3H), 1.51 (s, 3H), 1.37 (s, 3H);Anal. Calcd for C₂₇H₃₁N₃O₅S: C, 63.63; H, 6.13; N, 8.24; S, 6.29. Found:C, 63.50; H, 6.33; N, 7.81; S, 5.68.

EXAMPLE A183-(2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoylamino}-4-phenyl-butanoyl)]-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-methylsulfanyl-phenyl)-amide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.41 (t, J=5.7, 1H), 8.10 (d, J=8.3,1H) 8.09-6.54 (m, 12H), 5.46 (d, J=6.6, 1H), 5.14 (d, J=9.2, 1H), 5.04(d, J=9.2, 1H), 4.50-4.02 (m, 4H), 4.50 (s, 1H), 2.89-2.69 (m, 2H), 2.51(s, 3H), 1.84 (s, 3H), 1.53 (s, 3H), 1.39 (s, 3H); Anal. Calcd forC₃₂H₃₇N₃O₅S₂: C, 63.24; H, 6.14; N, 6.91. Found: C, 63.01; H, 6.30; N,6.53.

EXAMPLE A19(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid phenethyl-amide

¹H NMR (DMSO-d₆) δ 9.41 (s, 1H), 8.38 (t, J=4.8, 1H), 8.16 (d, J=8.1,1H), 8.01 (d, J=7.4, 1H), 7.64 (m, 1H), 7.52 (m, 2H), 7.32-7.11 (m, 6H),6.93 (t, J=7.9, 1H), 6.76 (d, J=7.9, 1H), 6.54 (d, J=7.5, 1H), 5.42 (d,J=6.4, 1H), 5.10 (d, J=9.3, 1H), 5.05 (d, J=9.0, 1H), 4.80-4.32 (m, 5H),2.84-2.66 (m, 4H), 1.80 (s, 3H), 1.56 (s, 3H), 1.45 (s, 3H); Anal. Calcdfor C₃₂H₃₇N₃O₅S: C, 66.76; H, 6.48; N, 7.30. Found C, 66.50; H, 6.56; N,7.23.

EXAMPLE A20(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((S)-1-phenyl-ethyl)-amide

White solid: mp 114-115° C.; IR (neat, cm⁻¹) 3306, 2971, 1643, 1531,1451, 1372, 1284, 1211, 1107; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.45 (d,J=8.2, 1H), 8.19 (d, J=8.2, 1H), 7.32-7.18 (m, 10H), 6.96-6.91 (m, 1H),6.76 (d, J=8.1, 1H), 6.54 (d, J=7.5, 1H), 5.36 (d, J=7.2, 1H), 5.08 (d,J=9.7, 1H), 5.01 (d, J=9.7, 1H), 4.95-4.85 (m, 2H), 4.48 (s, 1H),4.45-4.30 (m, 1H), 2.80-2.60 (m, 2H), 1.79 (s, 3H), 1.47 (s, 3H), 1.36(d, J=7.2, 3H), 1.30 (d, J=7.0, 3H); Anal. Calcd for C₃₂H₃₇N₃O₅S.0.25H₂O: C, 66.24; H, 6.51; N, 7.24. Found C, 66.30; H, 6.56; N, 6.89.

EXAMPLE A21(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((R)-1-phenyl-ethyl)-amide

White solid: mp 114-115° C.; IR (neat, cm⁻¹) 3299, 1643, 1583, 1520,1454, 1377, 1284, 1104; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.36 (d, J=8.2,1H), 8.15 (d, J=8.2, 1H), 7.44-7.13 (m, 10H), 6.96-6.91 (m, 1H), 6.75(d, J=8.1, 1H), 6.52 (d, J=6.7, 1H), 5.38 (d, J=6.9, 1H), 5.15 (d,J=9.7, 1H), 4.99 (d, J=9.7, 1H), 5.28-4.74 (m, 1H), 4.52(s, 1H),4.49-4.35 (m, 2H), 2.80-2.60 (m, 2H), 1.79 (s, 3H), 1.50 (s, 3H), 1.38(s, 3H), 1.34 (d, J=7.0, 3H); Anal. Calcd for C₃₂H₃₇N₃O₅S.0.25 H₂O: C,66.24; H, 6.51; N, 7.24. Found: C, 66.38; H, 6.52; N, 7.30.

EXAMPLE A223-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (benzo[1,3]dioxol-5-ylmethyl)-amide

IR (neat or KBr cm⁻¹) 3302, 2922, 2351, 2333, 1768, 1750, 1646, 1537; ¹HNMR (DMSO-d₆) δ 9.36 (s, 1H), 8.44 (s, 1H), 8.13 (d, J=7.9 1H),7.34-7.13 (m, 5H), 6.99-6.77 (m, 4H), 6.78 (d, J=7.7, 1H), 5.93 (d,J=7.1, 2H), 5.15 (d, J=7.0, 1H), 5.08 (d, J=7.8, 1H), 4.43 (d, J=9.32,2H), 4.34 (m, 2H), 4.12(d, J=6.18, 1H), 4.08 (d, J=6.08, 1H), 2.86-2.67(m, 2H), 2.55 (s, 1H), 1.81 (s, 3H), 1.51 (s, 3H), 1.39 (s, 3H); Anal.Calcd C₃₂H₃₅N₃O₇S.0.65 TFA.1.0 H₂O: C, 57.31 H, 5.44 N, 6.02. Found: C,57.58 H, 5.47 N, 5.85.

EXAMPLE A23(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid allyl-methyl-amide

IR (neat, cm⁻¹) 3380, 2943, 1637, 1460, 1284, ¹H NMR (DMSO-d₆) δ 9.37(s, 1H), 8.24 (d, J=8.4, 1H), 7.34-7.15 (m, 5H), 6.94 (t, J=7.5, 1H),6.77 (d, J=7.7, 1H), 6.53 (d, J=7.5, 1H), 5.99 (m, 1H), 5.70-5.65 (m,1H), 5.49-5.00 (m, 5H), 4.30-3.85 (m, 4H), 3.08 (s, 3H), 2.78-2.65 (m,2H), 1.80 (s, 3H), 1.58 (s, 3H), 1.38 (s, 3H); HRMS (ESI) m/z calcd forC₂₈H₃₅N₃O₅SNa (M+Na)⁺ 548.2190, found 548.2178.

EXAMPLE A24(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid fluoro-trifluoromethyl-benzylamide

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.32 (t, J=6.0, 1H), 8.20 (d, J=8.4,1H), 7.70-7.56 (m, 3H), 7.37 (d, J=6.9, 2H), 7.27 (t, J=7.5, 2H), 7.18(t, J=7.4, 1H), 6.97 (t, J=7.0, 1H), 6.79 (d, J=7.0, 1H), 6.58 (d,J=6.6, 1H), 5.15 (d, J=9.0, 1H), 5.02 (d, J=9.0, 1H), 4.60-4.48 (m, 3H),4.48-4.32 (m, 2H), 2.88-2.65 (m, 2H), 1.83 (s, 3H), 1.48 (s, 3H), 1.34(s, 3H); HRMS (ESI) m/z calcd for C₃₂H₃₃N₃O₅SF₄Na (M+Na)⁺ 670.1969,found 670.1999; Anal. Calcd for C₃₂H₃₃N₃O₅S F₄.1 H₂O, 0.3 TFA: C, 55.94;H, 5.08; N, 6.00. Found: C, 55.74; H, 4.98; N, 5.94.

EXAMPLE A25(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-trifluoromethoxy-benzylamide

White solid: mp=102-105° C.; IR (cm⁻¹) 3306, 2966, 1644, 1586, 1520,1216, 1166; ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.53 (t, J=6.0, 1H), 8.12(d, J=8.1, 1H), 7.40-7.13 (m, 9H), 6.96-6.91 (m, 1H), 6.77 (d, J=8.2,1H), 6.54 (d, J=7.7, 1H), 5.48 (d, J=6.4, 1H), 5.13 (d, J=9.2, 1H), 5.00(d, J=9.2, 1H), 4.46-3.97 (m, 5H), 2.87-2.67 (m, 2H), 1.81 (s, 3H), 1.50(s, 3H), 1.30 (s, 3H); Anal. Calcd for C₃₂H₃₄F₃ N₃O₆S.0.25 H₂O: C,59.11; H, 5.35; N, 6.46. Found: C, 58.91; H, 5.40; N, 6.30.

EXAMPLE A26(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-ethoxy-benzylamide

White solid: mp=105-107° C.; IR (cm⁻¹) 3322, 3063, 2978, 1643, 1585,1538, 1454, 1354, 1265, 1159, 1050; ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H),8.40 (t, J=5.6, 1H), 8.11 (d, J=8.2, 1H), 7.30-6.70 (m, 11H), 6.53 (d,J=7.5, 1H), 5.48 (d, J=5.9, 1H), 5.11 (d, J=8.9, 1H), 5.00 (d, J=8.9,1H), 4.50-4.20 (m, 4H), 4.07 (dd, J=15.0, 5.3, 1H), 3.94 (dd, J=14.0,6.9, 2H), 2.90-2.62 (m, 2H), 1.81 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3 H),1.25 (t, J=6.9, 3H); Anal. Calcd for C₃₃H₃₉N₃O₆S.0.75 H₂O: C, 64.01; H,6.59; N, 6.79. Found: C, 63.89; H, 6.27; N, 6.44.

EXAMPLE A27(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid methyl-prop-2-ynyl-amide

IR (neat, cm⁻¹) 3378, 1643, 1461, 1279, 1108, ¹H NMR (DMSO-d₆) δ 9.37(s, 1H), 8.21 (d, J=9.2, 1H), 7.33-7.13 (m, 5H), 6.94 (t, J=7.7, 1H),6.78 (d, J=8.1, 1H), 6.52 (d, J=7.0, 1H), 5.45 (d, J=6.8, 1H), 5.16 (d,J=9.2, 1H), 5.02 (d, J=9.2, 1H), 4.98 (s, 1H), 4.47-4.13 (s, 3H),4.03-3.92 (m, 1H), 3.17 (s, 3H), 2.88 (s, 1H), 2.79-2.50 (m, 2H), 1.80(s, 3H), 1.57 (s, 3H), 1.36 (s, 3H); Anal. Calcd for C₂₈H₃₃N₃O₅S.0.6H₂O:C, 62.95; H, 6.45; N, 7.86. Found: C, 62.95; H, 6.39; N, 7.69.

EXAMPLE A28(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-methyl-allyl)-amide

¹H NMR (DMSO-d₆) δ 9.33, (s, 1H), 8.18-7.79 (m, 2H), 7.39-7.12 (m, 5H),6.92 (t, J=8.1, 1H), 6.75 (d, J=8.1, 1H), 6.53 (d, J=7.0, 1H), 5.09 (d,J=9.2, 1H), 4.96 (d, J=9.2, 1H), 4.70 (s, 1H), 4.43 (s, 1H), 4.40 (br s,2H) 3.81-3.49 (m, 4H), 2.85-2.65 (m, 2H), 1.82 (s, 3H), 1.63 (s, 3H),1.49 (s, 3H), 1.35 (s, 3H); Anal. Calcd for C₂₈H₃₅N₃O₅S: C, 63.97; H,6.71; N, 7.99. Found: C, 63.85; H, 6.92; N, 7.65.

EXAMPLE A29(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-amino-benzylamide

IR (neat, cm⁻¹) 3401, 2943, 1643, 1525, 1461, 1373; ¹H NMR (DMSO-d₆) δ9.36 (s, 1H), 8.28 (t, J=8.0, 1H), 8.12 (d, J=8.9, 1H), 7.33-6.37 (m,12H), 5.45 (d, J=7.0, 1H), 5.10 (d, J=8.9, 1H), 4.99 (d, J=8.9, 1H),4.50-4.35 (m, 3H), 4.30-3.90 (m 2H), 2.90-2.70 (m, 2H), 2.06 (s, 2H),1.81 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H); Anal. Calcd forC₃₁H₃₆N₄O₅S.0.5 H₂O: C, 63.57; H, 6.37; N, 9.57. Found: C, 63.59; H,6.38; N, 9.58.

EXAMPLE A30(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid cyanomethylamide

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.65 (s, 1H), 8.15 (m, 1H), 7.42-7.19(m, 5H), 6.94 (t, J=7.9, 1H), 6.81 (d, J=7.9, 1H), 6.62 (d, J=7.9, 1H),5.22 (d, J=9.7, 1H), 5.05 (d, J=9.7, 1H), 4.61-4.36 (m, 4H), 3.01-2.71(m, 4H), 1.84 (s, 3H), 1.47 (s, 3H), 1.34 (s, 3H); Anal. Calcd forC₂₆H₃₀N₄O₅S: C, 61.16; H, 5.92; N, 10.97. Found: C, 61.24; H, 6.14; N,10.62.

EXAMPLE A31(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (Z)-but-2-enylamide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.35 (m, 1H), 8.12 (m, 1H), 7.15-6.98(m, 6H), 6.77 (d, J=7.7, 1H), 6.68 (d, J=7.5, 1H), 5.60-5.33 (m, 3H),5.18 (d, J=9.2, 1H), 5.02 (d, J=9.2, 1H), 4.52-4.39 (m, 3H), 3.79-3.68(m, 2H), 2.92-2.62 (m, 2H), 1.80 (s, 3H), 1.61 (d, J=6.9, 3H), 1.51 (s,3H), 1.38 (s, 3H); Anal. Calcd for C₂₈H₃₅N₃O₅S: C, 63.97; H, 6.71; N,7.99. Found: C, 63.73; H, 6.75; N, 7.83.

EXAMPLE A32(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (3-methyl-but-2-enyl)-amide

¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 8.19 (d, J=8.6, 1H), 7.96 (s br, 1H),7.39-7.18 (m, 5H), 6.91 (t, J=7.6, 1H), 6.79 (d, J=7.9, 1H), 6.55 (d,J=7.1, 1H), 5.41 (m br, 1H), 5.21 (m, 2H), 5.02 (d, J=9.1, 1H),4.57-4.37 (m, 3H), 3.79-3.61 (m, 2H), 2.90-2.71 (m, 2H), 1.81 (s, 3H),1.63 (s, 6H), 1.52 (s, 3H), 1.40 (s, 3H); Anal. Calcd for C₂₉H₃₇N₃O₅S:C, 64.54; H, 6.91; N, 7.79. Found: C, 64.75; H, 6.82; N, 7.43.

EXAMPLE A33(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-acetylamino-benzylamide

White solid: mp=145-147° C.; IR (neat, cm⁻¹) 3378, 2919, 1637, 1514,1461, 1361; ¹H NMR (DMSO-d₆) δ 9.87 (s, 1H), 9.36 (s, 1H), 8.45-8.40 (m,1H), 8.12 (d, J=7.9, 1H), 7.49-6.91 (m, 10H), 6.77 (d, J=7.9, 1H), 6.55(d, J=7.9, 1H), 5.49 (d, J=7.0, 1H), 5.10 (d, J=9.3, 1H), 5.00 (d,J=9.3, 1H), 4.44-3.95 (m, 5H), 2.90-2.62 (m, 2H), 2.00 (s, 3H), 1.80 (s,3H), 1.48 (s, 3H), 1.32 (s, 3H); Anal. Calcd for C₃₂H₃₈N₄O₆S.1.5 H₂O: C,61.38; H, 6.40; N, 8.68. Found: C, 61.49; H, 6.14; N, 8.35.

EXAMPLE A34(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((Z)-2-methyl-but-2-enyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.16 (d, J=8.4, 1H), 8.00 (t, J=5.3,1H), 7.36-7.13 (m, 5H), 6.94 (t, J=7.7, 1H), 6.77 (d, J=8.1, 1H), 6.53(d, J=7.3, 1H), 5.37 (d, J=5.7, 1H), 5.24 (m, 1H), 5.12 (d, J=9.0, 1H),5.00 (d, J=9.0, 1H), 4.48-4.39 (m, 3H), 3.71 (d, J=3.7, 2H), 2.82-2.65(m, 2H), 1.80 (s, 3H), 1.61 (m, 6H), 1.49 (s, 3H), 1.35 (s, 3H); HRMS(ESI) m/z calcd for C₂₉H₃₇N₃O₅SNa (M+Na)⁺ 562.2346, found 562.2360;Anal. Calcd for C₂₉H₃₇N₃O₅S: C, 64.54; H, 6.91; N, 7.79. Found: C,64.33; H, 6.92; N, 7.60.

EXAMPLE A35(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((E)-2-methyl-but-2-enyl)-amide

¹H NMR (DMSO-d₆) δ 9.37(s, 1H), 8.11 (d, J=8.2, 1H), 7.96 (t, J=5.5,1H), 7.34-7.13 (m, 5H), 6.94 (t, J=7.7, 1H), 6.77 (d, J=8.1, 1H), 6.53(d, J=7.3, 1H), 5.44 (d, J=6.6, 1H), 5.34 (d, J=6.6, 1H), 5.10 (d,J=9.0, 1H), 4.98 (d, J=9.1, 1H), 4.47-4.36 (m, 3H), 3.71 (dd, J=14.7,6.6, 1H), 3.46 (dd, J=14.5, 4.8, 1H), 2.85-2.67 (m, 2H), 1.81 (s, 3H),1.50 (m, 9H), 1.35 (s, 3H); HRMS (ESI) m/z calcd for C₂₉H₃₇N₃O₅SNa(M+Na)⁺ 562.2346, found 562.2220.

EXAMPLE A36(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (E)-pent-2-enylamide

White solid: mp=113-115° C.; IR (neat, cm⁻¹) 3315, 2964, 1643, 1584,1530, 1454, 1371, 1283, 1104, 969; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.11(d, J=8.2, 1H), 8.02 (t, J=5.6, 1H), 7.33-7.13 (m, 5H), 6.96-6.90 (m,1H), 6.76 (d, J=8.2, 1H), 6.52 (d, J=7.5, 1H), 5.66-5.56 (m, 1H),5.43(d, J=6.8, 1H), 5.38-5.31 (m, 1H), 5.10 (d, J=8.9, 1H), 4.99 (d,J=8.9, 1H), 4.47-4.39 (m, 2H), 4.38 (s, 1H), 3.72-3.53 (m, 2H),2.84-2.66 (m, 2H), 1.98-1.83 (m, 2H), 1.80 (s, 3H), 1.48 (s, 3H), 1.34(s, 3H), 0.87 (t, J=7.3, 3H); Anal. Calcd for C₂₉H₃₇N₃O₅S.0 5 H₂O: C,63.48; H, 6.98; N, 7.66. Found: C, 63.30; H, 7.00; N, 7.28.

EXAMPLE A37(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (Z)-pent-2-enylamide

White solid: mp=112-113° C.; IR (neat, cm⁻¹) 3320, 2965, 1659, 1643,1538, 1455, 1372, 1285, 1210, 1105, 1048; ¹H NMR (DMSO-d₆) δ 9.35 (s,1H), 8.11 (d, J=7.9, 1H), 8.03 (t, J=5.3, 1H), 7.35-7.13 (m, 5H),6.96-6.90 (m, 1H), 6.76 (d, J=8.1, 1H), 6.53 (d, J=7.3, 1H), 5.42 (d,J=6.7, 1H), 5.37-5.35 (m, 1H), 5.29-5.23 (m, 1H), 5.09 (d, J=9.2, 1H),4.99 (d, J=9.2, 1H), 4.45-4.38 (m, 2H), 4.36 (s, 1H), 3.80-3.62 (m, 2H),2.84-2.70 (m, 2H), 2.07-1.97 (m, 2H), 1.80 (s, 3H), 1.48 (s, 3H), 1.34(s, 3H), 0.90 (t, J=7.5, 3H); Anal. Calcd for C₂₉H₃₇N₃O₅S.0 5 H₂O: C,63.48; H, 6.98; N, 7.66. Found: C, 63.60; H, 6.92; N, 7.48.

EXAMPLE A38(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (E)-but-2-enylamide

¹H NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.19 (m br, 1H), 8.03 (m br, 1H),7.40-7.16 (m, 5H), 6.94 (t, J=7.1, 1H), 6.79 (d, J=7.7, 1H), 6.55 (d,J=7.5, 1H), 5.64-5.31 (m, 3H), 5.19 (d, J=9.2, 1H), 5.02 (d, J=9.2, 1H),4.55-4.38 (m, 3H), 3.80-3.69 (m, 2H), 2.84-2.70 (m, 2H), 1.80 (s, 3H),1.61 (s br, 3H), 1.51 (s, 3H), 1.39 (s, 3H); Anal. Calcd forC₂₈H₃₅N₃O₅S: C, 63.73; H, 7.07; N, 7.96. Found: C, 63.41; H, 7.23; N, 7.71.

EXAMPLE A39(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-dimethylamino-benzylamide

White solid: mp=105-106° C.; IR (neat, cm⁻¹) 2219, 2966, 1732, 1644,1585, 1531, 1494, 1454, 1373, 1264, 1047; ¹H NMR (DMSO-d₆) δ 9.37 (s,1H), 8.33 (t, J=6.1, 1H), 8.08 (d, J=8.1, 1H), 7.32-6.52 (m, 12H), 5.54(d, J=6.0, 1H), 5.10 (d, J=9.2, 1H), 4.99 (d, J=9.2, 1H), 4.43-4.31 (m,4H), 4.03 (dd, J=15.3, 5.3, 1H), 2.84 (s, 6H), 2.84-2.67 (m, 2H), 1.81(s, 3H), 1.49 (s, 3H), 1.35 (s, 3H). Anal. Calcd for C₃₃H₄₀N₄O₅S.0.1H₂O: C, 65.35; H, 6.68; N, 9.24. Found: C, 65.49; H, 6.67; N, 9.30.

EXAMPLE A40(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid ((E)-4,4,4-trifluoro-but-2-enyl)-amide

White foam; IR (neat, cm⁻¹) 3332, 1661, 1641, 1584, 1531, 1443, 1280,1119; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.32 (t, J=5.6, 1H), 8.15 (d,J=8.4, 1H), 7.35-7.12 (m, 5H), 7.00-6.90 (m, 1H), 6.77 (d, J=7.3, 1H),6.52 (d, J=7.3, 1H), 6.49-6.40 (m, 1H), 6.08-6.00 (m, 1H), 5.49(d,J=6.4, 1H), 5.15 (d, J=9.2, 1H), 5.01 (d, J=9.2, 1H), 4.50-4.40 (m, 2H),4.38 (s, 1H), 4.10-3.90 (m, 1H), 3.80-3.70 (m, 1H), 2.90-2.60 (m, 2H),1.80 (s, 3H), 1.51 (s, 3H), 1.34 (s, 3H); Anal. Calcd for C₂₈H₃₂F₃N₃O₅S:C, 58.02; H, 5.56; N, 7.25. Found: C, 58.37; H, 5.70; N, 6.91.

EXAMPLE A41(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (1-cyano-1,1-dimethyl-methyl)-amide

¹H NMR (DMSO-d₆) δ 9.39 (s, 1H), 8.31-8.12 (m, 2H), 7.38-7.17 (m, 5H),6.97 (t, J=7.3, 1H), 6.79 (d, J=7.7, 1H), 6.59 (d, J=7.4, 1H), 5.41 (mbr, 1H), 5.21 (d, J=9.2, 1H), 5.00 (d, J=9.2, 1H), 4.58-4.35 (m, 3H),2.85-2.62 (m, 2H), 1.81 (s, 3H), 1.62 (s, 6H), 1.47 (s, 3H), 1.39 (s,3H); Anal. Calcd for C₂₈H₃₄N₄O₅S: C, 62.43; H, 6.36; N, 10.40. Found: C,62.12; H, 6.55; N, 10.13.

EXAMPLE A42(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-hydroxy-benzylamide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 9.30 (s, 1H), 8.35 (t, J=5.9, 1H), 8.11(d, J=8.1, 1H), 7.33-7.15 (m, 5H), 7.04 (t, J=7.7, 1H), 6.94 (t, J=7.9,1H), 6.77 (d, J=8.1, 1H), 6.70-6.54 (m, 4H), 5.49 (s br, 1H), 5.11 (d,J=9.2, 1H), 5.00 (d, J=9.3, 1H), 4.43 (m, 3H), 4.27 (dd, J=15.2, 6.0,1H), 4.07 (dd, J=15.0, 5.5, 1H), 2.88-2.67 (m, 2H), 1.82 (s, 3H), 1.49(s, 3H), 1.33 (s, 3H); Anal. Calcd for C₃₁H₃₅N₃O₆S.H₂O: C, 62.50; H,6.26; N, 7.05. Found: C, 62.66; H, 6.19; N, 6.83.

EXAMPLE A43(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-propoxy-benzylamide

White foam; IR (cm⁻¹) 3319, 2966, 1644, 1585, 1531, 1454, 1373, 1264,1047; ¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.40 (t, J=5.8, 1H), 8.10 (d,J=8.4, 1H), 7.31-6.71 (m, 11H), 6.53 (d, J=7.3, 1H), 5.46 (d, J=6.4,1H), 5.12 (d, J=9.2, 1H), 5.00 (d, J=9.2, 1H), 4.50-4.20 (m, 4H),4.11-3.83 (m, 3H), 2.90-2.62 (m, 2H), 1.81 (s, 3H), 1.72-1.60 (m, 2H),1.49 (s, 3H), 1.34 (s, 3H), 0.92 (t, J=7.3, 3H). Anal. Calcd forC₃₄H₄₁N₃O₆S.0.25 H₂O: C, 65.42; H, 6.70; N, 6.73. Found: C, 65.49; H,6.67; N, 6.70.

EXAMPLE A44(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-hydroxy-benzylamide

¹H NMR (DMSO-d₆) δ 9.50 (s, 1H), 9.36 (s, 1H), 8.33 (t, J=5.5, 1H), 8.14(d, J=8.2, 1H), 7.32-7.12 (m, 6H), 7.04-6.91 (m, 2H), 6.76 (m, 2H), 6.68(t, J=7.5, 1H), 6.54 (d, J=7.5, 1H), 5.46 (d, J=6.6, 1H), 5.13 (d,J=9.2, 1H), 5.01 (d, J=9.3, 1H), 4.47 (m, 3H), 4.28-4.19 (m, 2H),2.86-2.67 (m, 2H), 1.82 (s, 3H), 1.49 (s, 3H), 1.32 (s, 3H); HRMS (ESI)m/z calcd for C₃₁H₃₆N₃O₆S (M+H)⁺ 578.2325, found 578.2325.

EXAMPLE A45(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (3,3,3-trifluoro-propyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.20 (t, J=5.5, 1H), 8.13 (d, J=8.2,1H), 7.34-7.13 (m, 5H), 6.93 (t, J=7.7, 1H), 6.76 (d, J=8.1, 1H), 6.08(d, J=7.5, 1H), 5.44 (d, J=6.8, 1H), 5.10 (d, J=9.2, 1H), 5.05 (d,J=9.2, 1H), 4.48-4.38 (m, 2H), 4.35 (s, 1H), 3.32-3.25 (m, 2H),2.75-2.70 (m, 2H), 2.44-2.35 (m, 2H), 1.80 (s, 3H), 1.49 (s, 3H), 1.34(s, 3H); HRMS (ESI) m/z calcd for C₂₇H₃₃N₃O₅SF₃ (M+H)⁺ 568.2093, found568.2118.

EXAMPLE A46(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid methyl-propyl-amide

White solid: mp=108-110° C.; IR (cm⁻¹) 3325, 2964, 1637, 1522, 1456,1372, 1284; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.22 (d, J=8.6, 1H),7.34-7.12 (m, 5H), 6.96-6.90 (m, 1H), 6.77-6.75 (m, 1H), 6.53-6.50 (m,1H), 5.46 (d, J=6.4, 1H), 5.18-4.70 (m, 3H), 4.48-4.20 (m, 2H), 3.31 (s,3H), 2.90-2.50 (m, 2H), 1.80 (s, 3H), 1.80-1.77 (m, 2H), 1.56 (s, 3H),1.56-1.36 (m, 2H), 1.37 (s, 3H), 0.79 (t, J=7.5, 3H). Anal. Calcd forC₂₈H₃₇N₃O₅S.1.0 H₂O: C, 61.63; H, 7.20; N, 7.60. Found: C, 62.03; H,6.93; N, 7.33.

EXAMPLE A47(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 4-trifluoromethoxy-benzylamide

White solid: ¹H NMR (DMSO) δ 9.37 (s, 1H), 8.51 (t, J=5.9, 1H), 8.13 (d,J=7.3, 1H), 7.39 (d, J=8.6, 1H), 7.32-7.10 (m, 8H), 7.00-6.90 (m, 1H),6.76 (d, J=8.2, 1H), 6.53 (d, J=7.3, 1H), 5.49 (d, J=6.6, 1H), 5.14 (d,J=9.3, 1H), 5.00 (d, J=9.3, 1H), 4.49-4.37 (m, 4H), 4.17 (dd, J=15.0,5.7, 1H), 2.90-2.64 (m, 2H), 1.81 (s, 3H), 1.49 (s, 3H), 1.32 (s, 3H);HRMS (ESI) m/z calcd for C₃₂H₃₅N₃O₆F₃S (M+H)⁺ 646.2199, found 646.2184.

EXAMPLE A48(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-amide

¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.55 (t, J=5.8, 1H), 8.14 (d, J=8.4,1H), 7.29-7.11 (m, 8H), 6.94 (t, J=7.8, 1H), 6.77 (d, J=7.9, 1H), 6.54(d, J=7.4, 1H), 5.58 (d, J=8.2, 1H), 5.17 (d, J=9.2, 1H), 5.02 (d,J=9.2, 1H), 4.49-4.39 (m, 3H), 4.43 (s, 1H), 4.21 (dd, J=5.4, 15.3, 1H),2.83 (m, 1H), 2.71 (dd, J=13.5, 10.7, 1H), 2.20 (s, 3H), 1.51 (s, 3H),1.34 (s, 3H); HRMS (ESI) m/z calcd for C₃₂H₃₄F₂N₃O₇S (M+H)⁺ 642.2086,found 642.2099; Anal. Calcd for C₃₂H₃₃F₂N₃O₇S: C, 59.90; H, 5.18; N,6.55. Found: C, 60.01; H, 5.27; N, 6.29.

EXAMPLE A49(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-chloro-ethyl)-amide

¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.31 (t, 1H, J=5.5), 8.17 (d, 1H,J=8.4), 7.37-7.16 (m, 5H), 6.96 (t, 1H, J=7.9), 6.79 (d, 1H, J=8.1),6.55 (d, 1H, J=7.5), 5.47 (d, 1H, J=6.8), 5.11 (d, 1H, J=9.3), 5.03 (d,1H, J=9.3), 4.50-4.45 (m, 2H), 4.41 (s, 1H), 3.64-3.58 (m, 2H),3.46-3.34 (m, 2H), 2.86-2.69 (m, 2H), 1.82 (s, 3H), 1.53 (s, 3H), 1.40(s, 3H). Exact mass calculated for C₂₆H₃₃N₃O₅SCl (M+H)⁺ 534.1829, found534.1841.

EXAMPLE A50(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-hydroxy-ethyl)-(2-methyl-benzyl)-amide

¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.29 (d, J=8.4, 1H), 7.42-6.87 (m,10H), 6.78 (d, J=7.1, 1H), 6.55 (d, J=6.8, 1H), 5.44 (d, J=6.8, 1H),5.26 (d, J=10.0, 1H), 5.08 (s, 1H), 5.04 (d, J=9.2, 1H), 4.82-4.67 (m,2H), 4.55-4.24 (m, 3H), 3.67 (m, 2H), 3.47 (m, 2H), 2.78 (m, 2H), 2.24(s, 3H), 1.82 (s, 3H), 1.61 (s, 3H), 1.45 (s, 3H); HRMS (ESI) m/z calcdfor C₃₄H₄₂N₃O₆S (M+H)⁺ 620.2794, found 620.2798; Anal. Calcd forC₃₄H₄₁N₃O₆S. 1 H₂O: C, 64.03; H, 6.80; N, 6.59. Found: C, 63.66; H,6.40; N, 6.59.

EXAMPLE A513-[2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiiazolidine-4-carboxylicacid methyl-(2-ethyl-benzyl)-amide

White solid: ¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.45 (t, J=7.99, 1H), 8.10(d, J=8.1, 1H), 7.41-6.91 (m, 12H), 6.62 (d, J=7.8, 1H), 5.41 (d, J=6.8,1H), 5.12 (dd, J=8.1, 7.8, 1H), 4.44-4.35 (m, 3H), 4.42 (s, 1H),2.91-2.67 (m, 2H), 2.54-2.21 (q, J=6.89, 2H), 2.1 (s, 3H), 1.88 (s, 3H),1.56 (t, J=6.90, 3H), 1.49 (s, 3H), 1.34 (s, 3 H); Anal.(C₃₄H₄₁N₃O₅S.0.75 H₂O) calculated C (62.34), H (6.43), N (6.23), found C(62.72), H (6.52), N (5.97). HRMS (ESI) m/z calcd for 604.2845, found604.2845.

EXAMPLE A523-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid (2-methylamino-ethyl)-amide

White solid: ¹H NMR (DMSO-d₆) δ 9.40 (s, 1H), 8.45-8.01 (m, 1H),7.41-7.13 (m, 12H), 6.98 (t, J=7.8, 1H), 6.78 (d, J=6.85, 1H), 6.55 (d,J=6.99, 1H), 5.41 (m, 1H), 5.12-4.98 (m, 2H), 4.44-4.35 (m, 2H), 3.15(m, 2H), 2.91-2.67 (m, 2H), 1.84 (s, 3H), 1.66 (q, J=8.2, 4H), 1.34 (s,3H); Anal. (C₂₇H₃₆N₄O₅S.0.50 H₂O) calculated C (60.31), H (6.94), N(10.42), found C (60.59), H (6.50), N (8.08). HRMS (ESI) m/z calcd for556.2771, found 556.2770.

Amides of the general structure 3 (synthesized in the same manor as inthe Methods A section) are coupled to boc-protected acid 15, and exposedto methane sulfonic acid to yield amines 16. Subjecting amines 16 to thereaction conditions depicted yielded a series of amides 17 and ureas 19.

Synthesis of amines of the general type 16.16a

The title compound was prepared as follows.(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1(1.95 g, 7.47 mmol) was dissolved in EtOAc (25 mL) and cooled to 0° C.Diphenyl chlorophosphate (1.71 mL, 8.23 mmol) was added followed by TEA(1.14 mL, 8.23 mmol). The reaction was stirred at 0° C. for 1 h, andtreated with (S)-Cyclohex-2-enylamine (0.8 g, 8.23 mmol). The reactionmixture was stirred at room temperature overnight, then partitionedbetween 1N HCl (25 mL) and EtOAc (30 mL). The organic layer was washedwith saturated NaHCO₃, brine, dried over Na₂SO₄ and concentrated to ayellow oil. The resulting oil (2.54 g, 7.47 mmol) was dissolved in EtOAc(30 mL) and then cooled to 0° C. Methanesulfonic acid (2.27 mL, 33.62mmol) was added and the solution was stirred at 0° C. for 15 minutes,then at room temperature for 4 h. The mixture was re-cooled to 0° C. andquenched with 10% Na₂CO₃ (30 mL) then extracted with EtOAc (30 mL).Organic layer was washed with brine, dried over Na₂SO₄ and concentratedin vacuo to give a yellow oil 3. The resulting yellow oil (1.86 g, 7.74mmol) was dissolved in EtOAc (77 mL). BOC-AHPBA 4 (2.29 g, 7.74 mmol)was added followed by HOBt (1.05 g, 7.74 mmol). The mixture was stirredat room temperature 1 h, then cooled to 0° C. DCC (1.60 g, 7.74 mmol)was slowly added as solution in EtOAc (30 mL). The mixture was allowedto gradually warm to room temperature and stirred overnight. The mixturewas filtered and the filtrate was washed with 1N HCl (40 mL), saturatedNaHCO₃ (40 mL), brine (40 mL), dried over Na₂SO₄ and concentrated togive a crude white solid (contaminated with DCU). The DCU was removed byflash chromatography (30% to 50% EtOAc in hexanes) to provide a whitesolid (4 g, 7.73 mmol), which was dissolved in EtOAc (30 mL) and thencooled to 0° C. Methanesulfonic acid (2.35 mL, 34.76 mmol) was added andthe solution was stirred at 0° C. for 15 minutes, then at roomtemperature for 3 h. The mixture was re-cooled to 0° C. and quenchedwith 10% Na₂CO₃ (35 mL) then extracted with EtOAc (30 mL). Organic layerwas washed with brine, dried over Na₂SO₄ and concentrated in vacuo togive a material which was recrystalized from 60% EtOAc in hexanes toprovide the titled compound (2.41 g, 80%) as a white solid. ¹H NMR(DMSO-d₆) δ 8.21 (d, J=8.1, 1H), 7.31-7.17 (m, 5H), 5.80 (d, J=5.6, 1H),5.52-5.48 (m, 2H), 5.30-5.25 (m, 2H), 4.89 (s, 2H), 4.26 (s, 1H),4.21-4.00 (m, 3H), 3.15-2.70 (m, 2H), 2.50-2.00 (m, 2H), 2.00-1.00 (m,4H), 1.49 (s, 3H), 1.31 (s, 3H); Anal. Calcd for C₂₂H₃₁N₃O₃S: C, 63.28;H, 7.48; N, 10.06. Found: C, 63.40; H, 7.20; N, 9.98.

The following amines a-h were prepared by the specific method outlinedabove using the requisite amine.16a

¹H NMR (DMSO-d₆) δ 8.36 (t, J=6.0, 1H), 7.36-7.14 (m, 5H), 5.70 (m, 1H),5.34 (s br, 1H), 5.12 (d, J=17.0, 1H), 4.96-4.88 (m, 3H), 4.34 (s, 1H),4.10 (d, J=7.0, 1H), 3.80-3.55 (m, 2H), 3.06 (d, J=13.0, 1H), 2.87 (t,J=9.0, 1H), 2.38 (dd, J=13.0, 10.0, 1H), 1.52 (s, 3H), 1.33 (s, 3H).

16b

16c

¹H NMR (DMSO-d₆) δ 8.69 (t, J=5.3, 1H), 7.34-7.14 (m, 5H), 5.34 (s br,1H), 4.90 (s, 2H), 4.29 (s, 1H), 4.08 (d, J=7.0, 1H), 3.90-3.70 (m, 2H),3.07 (dd, J=13.4, 2.5, 1H), 2.96 (t, J=2.6, 1H), 2.88, (ddd, J=9.8, 8.0,2.8, 1H), 2.37 (dd, J=13.2, 9.9, 1H), 1.50 (s, 3H), 1.32 (s, 3H).16d

¹H NMR (DMSO-d₆) δ 8.13 (t, J=5.4, 1H), 7.35-7.15 (m, 5H), 5.28 (d,J=8.1, 1H), 4.79 (m, 2H), 4.27 (s, 1H), 4.07 (t, J=7.1, 1H), 3.10-2.71(m, 4H), 2.37 (dd, J=13.2, 9.9, 1H), 1.49 (s, 3H), 1.34 (m, 2H), 1.33(s, 3H), 0.77 (t, J=7.4,3H).16e

Isolated yield: 84%; MS (APCI, m/z): 461, 463 (M+H)16f

Isolated yield: 93%; MS (APCI, m/z): 464 (M+H).16 g

Isolated yield: 86%; MS (APCI, m/z): 496 (M+H).16 h

Isolated yield: 87%. MS-APCI (m/z+): 458.

Synthesis of Final Products of the General Type 17 from 16a-h, GeneralMethods:

Amide formation—To a solution of acid, amine 16 and HOBT in CH₂Cl₂ wasadded EDC and the solution stirred overnight at room temperature. Thesolution was concentrated in vacuo and the residue dissolved in ethylacetate and a small portion of water. The solution was washed withsaturated NH₄Cl or 0.5N HCl (2×), saturated NaHCO₃ (2×), brine (1×),dried with MgSO₄ and concentrated in vacuo. The resulting residuesubjected to flash silica gel chromatography or preparative HPLC toafford the desired product.

Urea formation #1—The corresponding amine and isocyanate (1.1-1.2 eq.)were taken in dichloromethane and stirred at room temperature undernitrogen. (1.5 hr to overnight). The solvent was then removed in vacuoand the resulting residue subjected to flash silica gel chromatographyor preparative HPLC to afford the desired product.

Urea formation #2—The corresponding amine was dissolved in CH₂Cl₂ andtreated with diisopropylethylamine (1.5 eq.) and phosgene (1 eq., 20%soln. in toluene) at −78° C. The resulting solution was warmed to roomtemperature and treated with the amine of general structure 16. Theresulting residue subjected to flash silica gel chromatography orpreparative HPLC to afford the desired product.

Specific Urea Synthesis EXAMPLE B13-(2-hydroxy-3-{[1-(3-hydroxy-pyrrolidin-yl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid-2-methyl-benzylamide

(R)-Pyrrolidin-3-ol (0.21 g, 2.40 mmol) was dissolved in dry CH₂Cl₂ (15mL) and cooled to −78° C. under argon with magnetic stirring. To thissolution was added Diisopropylethylamine (0.63 mL, 3.63 mmol) followedby Phosgene as a 20% solution in toluene (1.2 mL, 2.40 mmol). Theresulting yellow solution was stirred for 20 min at −78° C. then allowedto warm to room temperature. The solution was concentrated andre-dissolved in dry CH₂Cl₂ (5 mL) and THF (5 mL). To this was addedDiisopropylethylamine (0.31 mL, 1.81 mmol) followed by 16c. The resultwas stirred for 16 h at 23° C. then diluted with EtOAc (50 mL). Themixture was washed sequentially with 10% citric acid (1×50 mL),saturated NaHCO₃ (1×50 mL), H₂O (1×50 mL). The organics were dried overNa₂SO₄, filtered, and concentrated. The residue was purified by flashcolumn chromatography (5% MeOH in EtOAc) to yield the title compound(0.12 g, 18%) as a white foam.

¹H NMR (DMSO-d₆) δ 8.38 (t, J=5.7, 1H), 7.34-7.09 (m, 10H), 5.99 (d,J=8.3, 1H), 5.04 (d, J=9.5, 1H), 4.96 (d, J=9.5, 1H), 4.49 (s, 1H),4.48-4.38 (m, 3H), 4.22-3.83 (m, 4H), 3.29-3.04 (m, 3H), 2.77-2.70 (m,2H), 2.28 (s, 3H), 1.52 (s, 3H), 1.32 (s, 3H), 1.82-1.69 (m, 2H); HRMS(ESI) m/z calcd for C₂₉H₃₈N₄O₅SNa (M+Na)⁺ 577.2455, found 577.2440;Anal. Calcd for C₂₉H₃₈N₄O₅S.2H₂O: C, 58.96; H, 7.17; N, 9.48; S, 5.43.Found: C, 58.90; H, 6.40; N, 9.23; S, 5.24.

The following examples were prepared by the corresponding specificmethod outlined above using the requisite P2 fragment.

EXAMPLE B2 Isoxazole-5-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

White solid: mp=82-84° C.; IR (neat, cm⁻¹) 3313, 2967, 1656, 1538, 1454,1372, 1283, 1211, 1108, 916; ¹H NMR (DMSO-d₆) δ 8.91 (d, J=8.6, 1H),8.67 (d, J=2.0, 1H), 8.35 (t, J=5.0, 1H), 7.31-7.08 (m, 9H), 7.03 (d,J=2.0, 1H), 5.63 (d, J=6.9, 1H), 5.02 (d, J=8.6, 1H), 4.97 (d, J=8.6,1H), 4.60-4.30 (m, 4H), 4.14-4.00 (m, 1H), 2.90-2.75 (m, 2H), 2.23 (s,3H), 1.49 (s, 3H), 1.28 (s, 3H); HRMS (ESI) m/z calcd for C₂₈H₃₂N₄O₅SNa(M+Na)⁺ 559.1986, found 559.1994; Anal. Calcd for C₂₈H₃₂N₄O₅S.0.5H₂O: C,61.63; H, 6.10; N, 10.27. Found: C, 61.40; H, 5.91; N, 9.97.

EXAMPLE B3 Isoxazole-3-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

White solid; IR (neat, cm⁻¹) 3436, 1643, 1537, 1425, 1378; ¹H NMR(DMSO-d₆) δ 9.03 (s, 1H), 8.66 (d, J=8.7, 1H), 8.32 (t, J=5.3, 1H),7.30-7.1 1 (m, 9H), 6.79 (s, 1H), 5.67 (d, J=6.8, 1H), 4.97 (s, 2H),4.47-4.32 (m, 4H), 4.09 (dd, J=15.0, 5.0, 1H), 2.84 (m, 2H), 2.24 (s,3H), 1.49 (s, 3H), 1.34 (m, 3H); HRMS (ESI) m/z calcd for C₂₈H₃₂N₄O₅SNa(M+Na)⁺ 559.1986, found 559.1980.

EXAMPLE B4 5-Chloro-isoxazole-3-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

White solid; IR (neat, cm⁻¹) 3320, 2969, 1657, 1547, 1434, 1372, 1266;¹H NMR (DMSO-d₆) δ 8.74 (d, J=8.2, 1H), 8.29 (t, J=5.5, 1H), 7.28-7.08(m, 9H), 6.90 (s, 1H), 5.72 (d, J=7. 1, 1H), 4.96 (s, 2H), 4.44 (m, 3H),4.32 (dd, J=15.2, 6.0, 1H), 4.09 (dd, J=15.2, 4.6, 1H), 2.85 (m, 2H),2.83 (s, 3H), 1.49 (s, 3H), 1.33 (s, 3H); HRMS (ESI) m/z calcd forC₂₈H₃₁N₄O₅SClNa (M+Na)⁺ 593.1596, found 593.1569.

EXAMPLE B5(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[(1-thiophen-2-yl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid: mp=98-101° C.; IR (neat, cm⁻¹) 3416, 1644, 1538, 1455,1372, 1291, 1107; ¹H NMR (DMSO-d₆) δ 8.56 (d, J=8.0, 1H), 8.38 (t,J=4.8, 1H), 7.85 (d, J=3.5, 1H), 7.69 (d, J=4.8, 1H), 7.36-7.08 (m,10H), 5.38 (d, J=7.2, 1H), 5.10 (d, J=8.8, 1H), 4.98 (d, J=8.8, 1H),4.54-4.20 (m, 5H), 2.90-2.70 (m, 2H), 2.25 (s, 3H), 1.49 (s, 3H), 1.34(s, 3H); HRMS (ESI) m/z calcd for C₂₉H₃₃N₃O₄S₂Na (M+Na)⁺ 574.1805, found574.1818; Anal. Calcd for C₂₉H₃₃N₃O₄S₂.0.75H₂O: C, 61.62; H, 6.15; N,7.43. Found: C, 61.31; H, 5.97; N, 7.28.

EXAMPLE B6(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[(1-thiophen-3-yl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid: mp=98-100° C.; IR (neat, cm⁻¹) 3312, 3086, 2966, 1644,1538, 1455, 1372, 1286, 1109; ¹H NMR (DMSO-d₆) δ 8.42-8.34 (m, 2H), 8.14(m, 1H), 7.54-7.06 (m, 1 H), 5.74 (d, J=9.3, 1H), 5.35 (d, J=6.8, 1H),4.99 (d, J=9.3, 1H), 4.53 (d, J=3.0, 1H), 4.50 (s, 1H), 4.42 (dd,J=15.0, 7.0, 1H), 4.40-4.30 (m, 1H), 4.15 (dd, J=15.0, 5.0, 1H),2.90-2.70 (m, 2H), 2.26 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI)m/z calcd for C₂₉H₃₃N₃O₄S₂Na (M+Na)⁺ 574.1805, found 574.1789; Anal.Calcd for C₂₉H₃₃N₃O₄S₂.1H₂O: C, 61.14; H, 6.19; N, 7.38. Found: C,60.74; H, 5.90; N, 7.15.

EXAMPLE B7(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[((S)-1-tetrahydro-furan-2-yl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid: mp=82-84° C.; IR (neat, cm⁻¹) 3314, 2969, 1651, 1531, 1456,1372, 1109, 1071; ¹H NMR (DMSO-d₆) δ 8.35 (t, J=6.0, 1H), 7.60 (d,J=9.2, 1H), 7.31-7.09 (m, 9H), 5.45 (d, J=6.8, 1H), 4.97 (d, J=9.5, 1H),4.93 (d, J=9.5, 1H), 4.46 (s, 1H), 4.41-4.07 (m, 4H), 3.77-3.65 (m, 3H),2.78-2.64 (m, 2H), 2.26 (s, 3H), 2.00-1.80 (m, 1H), 1.60 (m, 1H), 1.49(s, 3H), 1.44-1.38 (m, 2H), 1.34 (s, 3H); HRMS (ESI) m/z calcd forC₂₉H₃₇N₃O₅SNa (M+Na)⁺ 562.2346, found 562.2345; Anal. Calcd forC₂₉H₃₇N₃O₅S.0.5 H₂O: C, 63.48; H, 6.98; N, 7.66. Found: C, 63.61; H,6.85; N, 7.58.

EXAMPLE B83-(2-hydroxy-3-{[1-(3-hydroxy-pyrrolidin-yl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid-2-methyl-benzylamide

¹H NMR (DMSO-d₆) δ 8.38 (t, J=5.5, 1H), 7.34-7.09 (m, 10H), 5.99 (d,J=8.2, 1H), 5.04 (d, J=9.5, 1H), 4.96 (d, J=9.5, 1H), 4.49 (s, 1H),4.48-4.38 (m, 3H), 4.35-4.16 (m, 3H), 4.00 (m, 1H), 3.29-3.04 (m, 3H),2.78-2.70 (m, 2H), 2.28 (s, 3H), 1.83-1.65 (m, 2H), 1.52 (s, 3H), 1.36(s, 3H); HRMS (ESI) m/z calcd for C₂₉H₃₈N₄O₅SNa (M+Na)⁺ 577.2455, found577.2473; Anal. Calcd for C₂₉H₃₈N₄O₅S.2H₂O: C, 58.96; N, 9.48. Found: C,58.68; N, 9.11.

EXAMPLE B9(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[((R)-1-tetrahydro-furan-2-yl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid; IR (neat, cm⁻¹) 3324, 2959, 2873, 1724, 1651, 1526, 1455,1372, 1289, 1073; ¹H NMR (DMSO-d₆) δ 8.35 (t, J=4.9, 1H), 7.77 (d,J=8.9, 1H), 7.52-7.09 (m, 9H), 5.51 (d, J=6.6, 1H), 4.97-4.89 (m, 2H),4.52-3.66 (m, 8H), 2.90-2.60 (m, 2H), 2.25 (s, 3H), 1.99-1.63 (m, 4H),1.48 (s, 3H), 1.33 (s, 3H); HRMS (ESI) m/z calcd for C₂₉H₃₇N₃O₅SNa(M+Na)⁺ 562.2346, found 562.2366. Anal. Calcd for C₂₉H₃₇N₃O₅S.0.25 H₂O:C, 64.01; H, 6.95; N, 7.72. Found: C, 64.20; H, 6.90; N, 7.82.

EXAMPLE B10 3,5-Dimethyl-isoxazole-4-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 92%; 1H-NMR (400 MHz, dmso-d₆): δ 8.38 (t, 1H), 8.13 (d,1H), 7.04-7.35 (m, 10H), 5.52 (d, 1H), 5.09 (d, 1H), 5.0 (d, 1H), 4.53(m, 1H), 4.5 (s, 1H), 4.48 (m, 2H), 4.17 (dd, 1H), 2.87 (dd, 1H), 2.7(q, 1H), 2.26 (s, 6H), 2.09 (s, 3H), 1.52 (s, 3H), 1.35 (s, 3H); IR (KBrin cm−1): 3313, 1643, 1521, 743; MS (APCI, m/z): 565 (M+H), 519, 265;C30H36N4O5S1.0.69 H₂O Calculated: C62.43, H6.53, N9.71, Observed:C63.81, H6.43, N9.92; HPLC: Rf (min.) 20.167; Purity: 98%.

EXAMPLE B11 2,4-Dimethyl-thiazole-5-carboxylic acid{1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 80%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 8.14 (d,1H), 7.0-7.35 (m, 10H), 5.48 (d, 1H), 5.04 (d, 1H), 5.0 (d, 1H), 4.52(m, 1H), 4.4 (s, 1H), 4.35 (m, 2H), 4.14 (dd, 1H), 2.78 (d, 2H), 2.57(s, 3H), 2.30 (s, 3H), 2.26 (s, 3H), 1.48 (s, 3H), 1.35 (s, 3H); IR (KBrin cm−1): 3310, 1641, 1534, 743; MS (APCI, m/z): 581 (M+H), 317, 265,259; C30H36N4O4S2.0.39 H₂O Calculated: C61.30, H6.31, N9.53, Observed:C62.04, H6.25, N9.65; HPLC: Rf (min.) 19.613; Purity: 98%.

EXAMPLE B12(R)-3-{(2S,3S)-2-Hydroxy-3-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 82%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 7.91 (d,1H), 7.35-7.04 (m, 10H), 6.78 (s, 2H), 5.96 (s, 1H), 5.35 (d, 1H), 5.13(s, 1H), 5.0 (d, 1H), 4.48 (s, 2H), 4.38 (dd, 1H), 4.30 (m, 1H), 4.13(dd, 1H), 3.7 (s, 3H), 2.8 (m, 2H), 2.26 (s, 3H), 1.52 (s, 3H), 1.35 (s,3H); IR (KBr in cm−1): 3324, 1639, 1538, 735; MS (APCI, m/z): 549 (M+H),503, 382, 285; C30H36N4O4S1.2.44 H₂O Calculated: C60.80, H6.95, N9.45,Observed: C65.67, H6.61, N10.21; HPLC: Rf (min.) 20.745; Purity: 100%.

EXAMPLE B13(R)-3-{(2S,3S)-3-[(1,5-Dimethyl-1H-pyrazole-4-carbonyl)-amino]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 68%; 1H-NMR (400 MHz, dmso-d₆): δ 8.30 (t, 1H), 7.83 (d,1H), 7.31-7.04 (m, 10H), 6.30 (s, 1H), 5.48 (d, 1H), 4.92 (s, 2H),4.30-4.48 (m, 4H), 4.17 (dd, 1H), 3.7 (s, 3H), 2.74 (m, 2H), 2.26 (s,3H), 2.18 (s, 3H), 1.48 (s, 3H), 1.30 (s, 3H); IR (KBr in cm−1): 3313,1645, 1532,744; MS (APCI, m/z): 564 (M+H), 300, 272; C30H37N5O4S1.0.5H₂O Calculated: C62.86, H6.69, N12.22, Observed: C63.92, H6.62, N12.42;HPLC: Rf (min.) 19.724; Purity: 100%.

EXAMPLE B143-{(S)-3-[(5-Chloro-1,3-dimethyl-1H-pyrazole-4-carbonyl)-amino]-2-hydroxy-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 92%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 7.74 (d,1H), 7.30-7.0 (m, 10H), 5.44 (d, 1H), 4.96 (q, 2H), 4.48 (m, 1H), 4.35(m, 2H), 4.13 (dd, 1H), 2.74 (m, 2H), 2.22 (s, 3H), 2.09 (s, 3H), 1.48(s, 3H), 1.26 (s, 3H); IR (KBr in cm−1): 3438, 3313, 1693, 1649, 1513,1372, 754; MS (APCI, m/z): 598 (M+H), 334, 276, 174;C30H36N5O4S1Cl1.0.17 H2O Calculated: C59.93, H6.09, N11.65, Observed:C60.24, H6.07, N11.71; HPLC: Rf (min.) 19.829; Purity: 100%.

EXAMPLE B15 2-Amino-4-methyl-thiazole-5-carboxylic acid{(S)-1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 42%; 1H-NMR (400 MHz, dmso-d₆): δ 8.48 (brs, 1H), 8.35(brs, 1H), 7.44 (d, 1H), 7.35-7.04 (m, 9H), 6.91 (s, 1H), 5.37 (d, 1H),4.96 (q, 2H), 4.48-4.0 (m, 5H), 2,96 (m, 2H), 2.22 (2, 3H), 2.13 (s,3H), 1.48 (s, 3H), 1.30 (s, 3H); IR (KBr in cm−1): 3307, 1625, 1495; MS(APCI, m/z): 582 (M+H), 442, 318; C29H35N5O4S2Cl1 Calculated: C60.13,H6.5, N10.82, Observed: C59.87, H6.06, N12.04; HPLC: Rf(min.) 17.981;Purity: 98%.

EXAMPLE B163-[2-Hydroxy-3-(2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 76%; 1H-NMR (400 MHz, dmso-d₆): δ 8.31 (t, 1H), 8.22 (d,1H), 7.32-7.04 (m, 13H), 5.48 (d, 1H), 5.13 (d, 1H), 5.0 (d, 1H), 4.48(s, 2H), 4.38 (dd, 2H), 4.09 (dd, 1H), 2.83 (d, 1H), 2.70 (t, 1H), 2.26(s, 3H), 2.01 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H); IR (KBr in cm−1):3309, 1641, 1520, 742; MS (APCI, m/z): 560 (M+H), 514, 296, 265;C32H37N3O4S1. 0.64 H20 Calculated: C67.40, H6.59, N7.37, Observed:C68.79, H6.49, N7.52; HPLC: Rf (min.) 21.024; Purity: 98%.

EXAMPLE B173-[3-(2,3-Dimethyl-benzoylamino)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 72%; 1H-NMR (400 MHz, dmso-d₆): δ 8.33 (t, 1H), 8.22 (d,1H), 7.35-6.83 (m, 12H), 5.48 (d, 1H), 5.13 (d, 1H), 5.04 (d, 1H),4.48-4.30 (m, 4H), 4.09 (dd, 1H), 2.84 (d, 1H), 2.70 (t, 1H), 2.26 (s,3H), 2.17 (s, 3H), 1.87 (s, 3H), 1.48 (s, 3H), 1.30 (s, 3H); IR (KBr incm−1): 3307, 1640, 1515, 743 ; MS (APCI, m/z): 574 (M+H), 528, 310, 265;C33H39N3O4S1. 0.54 H2O Calculated: C68.05, H6.76, N7.21, Observed:C69.20, H6.76, N7.34; HPLC: Rf (min.) 21.449; Purity: 99%.

EXAMPLE B18 6-Oxo-1,4,5,6-tetrahydro-pyridazine-3-carboxylic acid{1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 67%; 1H-NMR (400 MHz, dmso-d₆): δ 8.35 (t, 1H), 8.09 (d,1H), 7.30-7.0 (m, 10H), 5.6 (d, 1H), 4.91 (d, 1H), 4.83 (d, 1H), 4.44(s, 1H), 4.30 (m, 3H), 4.17 (dd, 1H), 2.78 (d, 2H), 2.61 (t, 2H), 2.30(t, 2H), 2.22 (s, 3H), 1.48 (s, 3H), 1.30 (s, 3H); IR (KBr in cm−1):3306, 1650, 1521, 742 ; MS (APCI, m/z): 566 (M+H), 520, 265;C29H35N5O5S1. 0.7 H2O Calculated: C60.23, H6.34, N12.11, Observed:C61.57, H6.24, N12.38; HPLC: Rf (min.) 18.455; Purity: 97%.

EXAMPLE B19 2,4-Dimethyl-5-oxo-2,5-dihydro-isoxazole-3-carboxylic acid{1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 73%; 1H-NMR (400 MHz, dmso-d₆): δ 8.91 (d, 1H), 8.35 (t,1H), 7.30-7.04 (m, 9H), 5.70 (d, 1H), 5.0 (d, 2H), 4.44 (s+m, 3H), 4.31(dd, 1H), 4.13 (dd, 1H), 2.91 (s+m, 4H), 2.65 (t, 1H), 2.22 (s, 3H),1.52 (s, 3H), 1.48 (s, 3H), 1.30 (s, 3H); IR (KBr in cm−1): 3325,2932,1729, 1649, 1527,742; MS (APCI, m/z): 581 (M+H), 539, 493, 225;C30H36N4O6S1 Calculated: C62.29, H5.61, N9.19, Observed: C62.05, H6.25,N9.65; HPLC: Rf (min.) 19.638; Purity: 100%.

EXAMPLE B20(R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2,4-dimethyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

¹H NMR (DMSO-d₆) δ 8.23 (s, 1H), 8.10-8.03 (m, 2H), 7.33-7.12 (m, 5H),6.85 (d, J=7.7, 1H), 6.51 (d, J=7.7, 1H), 5.82-5.70 (m, 1H), 5.44 (d,J=6.8, 1H), 5.22-4.97 (m, 4H), 4.50-4.30 (m, 3H), 3.84-3.60 (m, 2H),2.84-2.66 (m, 2H), 2.13 (s, 3H), 1.85 (s, 3H), 1.49 (s, 3H), 1.35 (s,3H); HRMS (ESI) m/z calcd for C₂₈H₃₆N₃O₅S (M+H)⁺ 526.2376, found526.2380; Anal. Calcd for C₂₈H₃₅N₃O₅S.0.2 TFA: C, 62.19; H, 6.47; N,7.66. Found: C, 62.27; H, 6.78; N, 7.26.

EXAMPLE B213-(2-Hydroxy-3-{[1-(3-hydroxy-2,4-dimethyl-phenyl)-methyanoyl]-amino}-4-phenyl-butznoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid prop-2-ynylamide

¹H NMR (DMSO-d₆) δ 8.40 (t, J=5.4, 1H), 8.22 (s, 1H), 8.02 (d, J=8.2,1H), 7.35-6.52 (m, 7H), 5.44 (d, J=6.8, 1H), 5.10 (d, J=9.1, 1H), 5.02(d, J=9.1, 1H), 4.46-4.40 (m, 2H), 4.40 (s, 1H), 3.86 (s br, 2H), 3.08(t, J=1.8, 1H), 2.82-2.72 (m, 2H), 2.15 (s, 3H), 1.88 (s, 3H), 1.51 (s,3H), 1.37 (s, 3H); HRMS (ESI) m/z calcd for C₂₈H₃₄N₃O₅S (M+H)⁺ 524.2219,found 524.2219; Anal. Calcd for C₂₈H₃₃N₃O₅S.0.5H₂O: C, 63.13; H, 6.43;N, 7.89; S, 6.02. Found: C, 62.80; H, 6.64; N, 7.71; S, 5.69.

EXAMPLE B223-{2-Hydroxy-3-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-chloro-benzylamide

Isolated yield: 50%; 1H-NMR (400 MHz, dmso-d⁶): 6.40-7.40 (m, 11H), 6.00(m, 1H), 4.20-5.20 (m, 7H), 3.71, 3.54 (s 3H), 2.70-2.90 (m, 2H), 1.52(d, J=2.0 Hz, 3H), 1.32 (d, J=2.1 Hz, 3H); MS (APCI, m/z): 570 (M+H).

EXAMPLE B23 3,5-Dimethyl-isoxazole-4-carboxylic acid{1-benzyl-3-[4-(2-chloro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 55%; 1H-NMR (400 MHz, dmso-d⁶): 7.00-7.40 (m, 9H),4.36-5.08 (m, 7H), 2.70-2.90 (m, 2H), 2.34, 2.25 (s, 3H), 2.18, 2.12 (s,3H), 1.56 (d, J=8.5 Hz, 3H), 1.35 (d, J=6.2 Hz, 3H); MS (APCI, m/z): 586(M+H); C₂₉H₃₃ClN₄O₅S.0.42H₂O Calculated: C58.77, H5.75, N9.45, Observed:C58.37, H5.73, N9.19.

EXAMPLE B243-{2-Hydroxy-3-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2,6-difluoro-benzylamide

Isolated yield: 75%; 1H-NMR (400 MHz, dmso-d⁶): 6.40-7.40 (m, 10H), 6.00(m, 1H), 4.20-5.20 (m, 7H), 3.64, 3.61 (s 3H), 2.70-2.90 (m, 2H), 1.52,1.49 (s, 3H), 1.33, 1.29 (s, 3H); MS (APCI, m/z): 571 (M+H);C₂₉H₃₂F₂N₄O₄S Calculated: C61.04, H5.65, N9.82, Observed: C60.86, H5.94,N9.71.

EXAMPLE B25 3,5-Dimethyl-isoxazole-4-carboxylic acid{1-benzyl-3-[4-(2,6-difluoro-benzylcarbamoyl)-5,5-dimethyl-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 75%; 1H-NMR (400 MHz, dmso-d⁶): 6.60-7.40 (m, 8H),4.26-5.08 (m, 7H), 2.70-2.90 (m, 2H), 2.32, 2.28 (s, 3H), 2.16, 2.13 (s,3H), 1.56, 1.53 (s, 3H), 1.37, 1.34 (s, 3H); MS (APCI, m/z): 587 (M+H);C₂₉H₃₂F₂N₄O₅S Calculated: C59.37, H5.50, N9.55, Observed: C59.12, H5.88,N9.50.

EXAMPLE B263-{2-Hydroxy-3-[(1-methyl-1H-pyrrole-2-carbonyl)-amino]-4-phenyl-butyryl}-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-trifluoromethyl-benzylamide

Isolated yield: 83%; 1H-NMR (400 MHz, dmso-d⁶): 6.40-7.60 (m, 11H), 6.00(m, 1H), 4.20-5.20 (m, 7H), 3.70, 3.54 (s 3H), 2.70-2.90 (m, 2H), 1.52(s, 3H), 1.36, 1.29 (s, 3H); MS (APCI, m/z): 619 (M+H); C₃₀H₃₃F₃N₄O₄SCalculated: C59.79, H5.52, N9.30, Observed: C59.42, H5.55, N9.06.

EXAMPLE B27 3,5-Dimethyl-isoxazole-4-carboxylic acid{1-benzyl-3-[5,5-dimethyl-4-(2-trifluoromethyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

Isolated yield: 93%; 1H-NMR (400 MHz, dmso-d⁶): 7.05-7.60 (m, 9H),4.36-5.08 (m, 7H), 2.70-2.90 (m, 2H), 2.30, 2.21 (s, 3H), 2.15, 2.05 (s,3H), 1.54, 1.52 (s, 3H), 1.39, 1.32 (s, 3H); MS (APCI, m/z): 619 (M+H);C₃₀H₃₃F₃N₄O₅S Calculated: C58.24, H5.38, N9.06, Observed: C57.87, H5.68,N9.02.

EXAMPLE B28N-[(1S,2S)-3-(4-Allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl]-nicotinamide

White solid: ¹H NMR (DMSO-d₆) δ 8.81 (d, J=8.6, 1), 8.77 (d, J=6.2, 1H),8.12 (m, 1H), 7.99 (m, 1H), 7.63 (m, 1H), 7.32-7.12 (m, 7H), 5.78 (m,1H), 5.18 (m ,2H), 4.56(m ,3H), 4.40 (m, 4H), 2.87-2.67 (m, 2H), 1.49(s, 3H), 1.34 (s, 3H); Anal. (C₂₆H₃₂N₄O₄S.0.5 H₂O.0.5 TFA) calculated C(57.65), H (6.36), N (10.19), found C (57.73), H (5.91), N (10.15). HRMS(ESI) m/z calcd for 483.2075, found 497.2066.

EXAMPLE B293-[2-Hydroxy-3-(4-methoxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

Isolated yield: 56%. ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (t, 1H), 8.09 (d,1H), 7.33-7.27 (m, 3H), 7.23-7.19 (m, 2H), 7.15-7.08 (m, 5H), 6.69 (d,2H), 5.46 (d, 1H), 5.13 (d, 1H), 4.99 (d, 1H), 4.49 (s, 2H), 4.41-4.36(m, 2H), 4.10 (dd, 1H), 3.71 (s,3H), 2.84-2.81 (m, 1H), 2.72 (t, 1H),2.24 (s, 3H), 2.07 (s, 3H), 1.48 (s, 3H), 1.33 (s, 3H); MS-APCI (m/z+):326, 590 (M+H). HPLC: Rf(min.) 21.26; Purity: 100%; C₃₃H₃₉N₃O₅S₁.0.4H₂O: calcd: C66.40, H6.72, N7.04, found: C66.38, H6.71, N6.94.

EXAMPLE B30(R)-3-{(2S,3S)-2-Hydroxy-4-phenyl-3-[(1-o-tolyl-methanoyl)-amino]-butanoyl}-5,5-dimethyl-thiazolidine-4-carboxylicacid propylamide

IR (neat, cm⁻¹) 3318, 2964, 1642, 1530, 1445, 1372, ¹H NMR (DMSO) δ 8.21(d, J=8.4, 1H), 7.90 (t, J=5.6, 1H), 7.35-7.07 (m, 9H), 5.45 (d, J=6.8,1H), 5.09 (d, J=9.2, 1H), 5.00 (d, J=9.2, 1H), 4.50-4.38 (m, 2H), 4.37(s, 1H), 3.01 (q, J=6.9, 2H), 2.90-2.60 (m, 2H), 2.02 (s, 3H), 1.49 (s,3H), 1.44-1.35 (m, 2H), 1.34 (s, 3H), 0.82 (t, J=7.5, 3H); HRMS (ESI)m/z calcd for C₂₇H₃₆N₃O₄S (M+H)⁺ 498.2424, found 498.2427.

EXAMPLE B31(R)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid propylamide

White solid: ¹H NMR (DMSO) δ 8.34 (d, J=8.1, 1H), 7.91 (t, J=5.9, 1H),7.40-7.10 (m, 7H), 6.93 (d, J=6.9, 1H), 5.51 (d, J=6.2, 1H), 5.08 (d,J=8.8, 1H), 5.00 (d, J=8.8, 1H), 4.50-4.39 (m, 2H), 4.38 (s, 1H), 3.00(dd, J=12.3, 5.9, 2H), 2.90-2.60 (m, 2H), 1.89 (s, 3H), 1.49 (s, 3H),1.40-1.34 (m, 2H), 1.34 (s, 3H), 0.82 (t, J=7.7, 3H); HRMS (ESI) m/zcalcd for C₂₇H₃₅N₃O₄FS (M+H)⁺ 516.2332, found 516.2339.

EXAMPLE B32(R)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 3-methoxy-benzylamide

White solid: ¹H NMR (DMSO) δ 8.43 (t, J=5.9, 1H), 8.34 (d, J=8.1, 1H),7.31-6.72 (m, 12H), 5.57 (d, J=6.8, 1H), 5.12 (d, J=9.3, 1H), 5.01 (d,J=9.3, 1H), 4.50-4.30 (m, 4H), 4.12 (dd, J=15.7, 5.9, 1H), 3.69 (s, 3H),2.95-2.62 (m, 2H), 1.90 (s, 3H), 1.49 (s, 3H), 1.34 (s, 3H); HRMS (ESI)m/z calcd for C₃₂H₃₇N₃O₅SF (M+H)⁺ 594.2434, found 594.2438.

EXAMPLE B33(R)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

White solid: ¹H NMR (DMSO) δ 8.34 (d, J=8.3, 1H), 8.10 (t, J=5.7, 1H),7.40-6.90 (m, 8H), 5.81-5.69 (m, 1H), 5.54 (d, J=6.6, 1H), 5.30-4.90 (m,4H), 4.50-4.35 (m, 3H), 3.80-3.65 (m, 2H), 2.90-2.60 (m, 2H), 1.89 (s,3H), 1.49 (s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd for C₂₇H₃₃N₃O₄SF(M+H)⁺ 514.2182, found 514.2176.

EXAMPLE B343-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

¹H NMR (DMSO-d₆) δ 9.23 (s, 1H), 8.09 (m, 2H), 7.35-7.17 (m, 5H), 6.60(s, 1H), 6.37 (s, 1H), 5.74 (m, 1H), 5.41 (br s, 1H), 5.20 (dd, J=17.2,1.6, 1H), 5.11 (d, J=9.2, 1H), 5.02 (dd, J=10.2, 1.5, 1H), 5.00 (d,J=9.1, 1H), 4.46-4.37 (m, 3H), 3.79 (ddd, J=15.9, 5.5, 5.3, 1H), 3.63(ddd, J=15.9, 5.4, 5.3, 1H), 2.82 (dd, J=13.9, 0.3, 1H), 2.71 (dd,J=13.6, 10.7, 1H), 2.16 (s, 3H), 1.76 (s, 3H), 1.51 (s, 3H), 1.36 (s,3H); Anal. Calcd for C₂₈H₃₅N₄O₅S.0.3H₂O: C, 63.32; H, 6.76; N, 7.91,Found: C, 63.35; H, 6.70; N, 7.71.

EXAMPLE B353-[(2S,3S)-3-(5-Fluoro-3-hydroxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

¹H NMR (DMSO-d₆) δ 9.94 (s, 1H), 8.23 (d, J=8.2, 1H), 8.10 (t, J=5.6,1H), 7.33-7.17 (m, 5H), 6.58 (dd, J=10.6, 2.5, 1H), 6.32 (dd, J=8.8,2.5, 1H), 5.78 (m, 1H), 5.54 (br s, 1H), 5.21 (dd, J=17.2, 1.7, 1H),5.10 (d, J=9.1, 1H), 5.03 (dd, J=10.2, 1.5, 1H), 5.01 (d, J=9.1, 1H),4.50-4.42 (m, 3H), 3.78 (ddd, J=15.9, 5.4, 5.4, 1H), 3.63 (ddd, J=15.9,5.4, 5.3, 1H), 2.84 (dd, J=14.5, 3.3, 1H), 2.70 (dd, J=13.5, 10.3, 1H),1.75 (s, 3H), 1.50 (s, 3H), 1.36 (s, 3H); Anal. Calcd forC₂₇H₃₂FN₃O₅S.0.3H₂O: C, 60.61; H, 6.14; N, 7.85, Found: C, 60.63; H,6.08; N, 8.07.

EXAMPLE B36(R)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

¹H NMR (DMSO) δ 8.85-8.35 (m, 2H), 7.38-6.90 (m, 12H), 5.55 (d, J=5.9,1H), 5.12 (d, J=9.2, 1H), 5.01 (d, J=9.2, 1H), 4.58-4.32 (m, 4H), 4.10(dd, J=15.0, 4.6, 1H), 2.92-2.62 (m, 2H), 2.24 (s, 3H), 1.90 (s, 3H),1.49 (s, 3H), 1.34 (s, 3H); HRMS (ESI) m/z calcd for C₃₂H₃₇N₃O₄FS (M+H)⁺578.2489, found 578.2486; Anal. Calcd for C₃₂H₃₆N₃O₄FS.0.2 EtOAc: C,66.17; H, 6.37; N, 7.06. Found: C, 66.30; H, 6.54; N, 6.74.

EXAMPLE B37(R)-3-((2S,3S)-3-{[1-(4-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid: ¹H NMR (DMSO) δ 8.40-8.30 (m, 2H), 7.35-6.90 (m, 12H), 5.53(d, J=6.8, 1H), 5.13 (d, J=9.0, 1H), 5.00 (d, J=9.0, 1H), 4.48 (s, 1H),4.47-4.45 (m, 2H), 4.38 (dd, J=15.0, 5.9, 1H), 4.10 (dd, J=15.0, 4.8,1H), 2.90-2.62 (m, 2H), 2.24 (s, 3H), 2.04 (s, 3H), 1.48 (s, 3H), 1.33(s, 3H); HRMS (ESI) m z calcd for C₃₂H₃₇N₃O₄SF (M+H)⁺ 578.2463, found578.2489.

EXAMPLE B38 Nicotinic acid3-[(1S,2S)-3-((R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl]-2-methyl-phenylester

White solid: ¹H NMR (DMSO) δ 9.26 (dd, J=2.0, 0.9, 1H), 8.90 (dd, J=5.6,2.0, 1H), 8.47 (dt, J=7.9, 2.0, 1H), 8.40 (d, J=8.2, 1H), 8.1 (t, J=5.7,1H), 7.65 (ddd, J=7.9, 5.6, 0.9, 1H), 7.40-7.10 (m, 8H), 5.82-5.68 (m,1H), 5.6 (d, J=6.2, 1H), 5.30-4.90 (m, 4H), 4.50-4.40 (m, 2H), 4.40 (s,1H), 3.80-3.70 (m, 2H), 3.00-2.60 (m, 2H), 1.85 (s, 3H), 1.49 (s, 3H),1.34 (s, 3H).

EXAMPLE B39(R)-3-[(2S,3S)-2-Hydroxy-3-(4-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid: ¹H NMR (DMSO) δ 9.55 (s, 1H), 8.32 (t, J=4.9, 1H), 8.00 (d,J=8.4, 1H), 7.36-7.00 (m, 10H), 6.54-6.48 (m, 2H), 5.44 (d, J=6.6, 1H),5.13 (d, J=9.2, 1H), 4.99 (d, J=9.2, 1H), 4.50-4.32 (m, 4H), 4.11 (dd,J=15.0, 4.8, 1H), 3.50-2.80 (m, 2H), 2.25 (s, 3H), 2.04 (s, 3H), 1.49(s, 3H), 1.33 (s, 3H); Anal. Calcd for C₃₂H₃₇N₃O₅S.0.25 H₂O: C, 66.24;H, 6.51; N, 7.24. Found: C, 66.25; H, 6.55; N, 7.35.

EXAMPLE B40 6-Amino-pyridine-2-carboxylic acid{(1S,2S)-1-benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

¹H NMR (DMSO-d₆) δ 8.44 (d, 1H, J=5.6), 8.36 (d, 1H, J=9.3), 7.69-7.49(t, 1H, J=7.7), 7.34-7.06 (m, 10H), 6.61 (d, 1H, J=8.4), 6.27 (br s, 2H)5.47 (d, 1H, J=7.1), 5.00 (m, 2H), 4.54-4.43 (m, 2H), 4.50 (s, 1H), 4.38(dd, 1 H, J=6.4, 15.2), 4.19 (dd, 1H, J=4.6, 14.7), 2.87-2.65 (m, 2H),2.28 (s, 3H), 1.53 (s, 3H), 1.38 (s, 3H). Exact mass calculated forC₃₀H₃₆N₅O₄S (M+H)⁺ 562.2488, found 562.2493.

EXAMPLE B41{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-2,3-dichloro-isonicotinamide

¹H NMR (DMSO-d₆) δ 8.89 (d, 1H, J=8.42), 8.40 (t, 1H, J=5.5), 8.38 (d,1H, J=4.8), 7.30-7.08 (m, 10H), 5.58 (d, 1H, J=7.3), 5.07 (d, 1H,J=8.8), 5.00 (d, 1H, J=8.8), 4.54-4.50 (m, 1H), 4.51 (s, 1H), 4.43-4.36(m, 2H), 4.16 (dd, 1H, J=5.1, 15.0), 2.89-2.85 (m, 1H), 2.71-2.63 (m,1H), 2.26 (s, 3H), 1.50 (s, 3H), 1.35s (s, 3H). Exact mass calculatedfor C₃₀H₃₃N₄O₄SCl₂ (M+H)⁺ 615.1600, found 615.1581. Anal. Calcd forC₃₀H₃₂N₄O₄SCl₂: C, 58.54; H, 5.24; N, 9.10. Found: C, 58.48; H, 5.10; N,8.80.

EXAMPLE B42{(1S,2S)-1-Benzyl-3-[(R)-5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-3-chloro-isonicotinamide

¹H NMR (DMSO-d₆) δ 8.82 (d, 1H, J=8.6), 8.62 (s, 1H), 8.52 (d, 1H,J=4.9), 8.39 (d, 1H, J=5.1), 7.29-7.09 (m, 10H), 5.54 (d, 1H, J=7.1),5.09 (d, 1H, J=9.0), 4.99 (d, 1H, J=9.0), 4.56-4.49 (m, 1H), 4.51 (s,1H), 4.44-4.37 (m, 2H), 4.15 (dd, 1H, J=5.1, 15.0), 2.88-2.83 (m, 1H),2.74-2.65 (m, 1H), 2.26 (s, 3H), 1.50 (s, 3H), 1.35s (s, 3H). Exact masscalculated for C₃₀H₃₃N₄O₄SCl (M)⁺ 581.1989, found 581.1983.

EXAMPLE B43(R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid 2-methyl-benzylamide

¹H NMR (DMSO-d₆) δ 9.24 (s, 1H), 8.31 (t, J=5.6, 1H), 8.10 (d, J=8.2,1H), 7.34-7.09 (m, 9H), 6.60 (s, 1H), 6.38 (s, 1H), 5.42 (br s, 1H),5.14 (d, J=9.1, 1H), 5.01 (d, J=9.1, 1H), 4.50 (s, 1H), 4.50-4.37 (m,3H), 4.11 (dd, J=15.1, 4.7, 1H), 2.76 (m, 2H), 2.26 (s, 3H), 2.16 (s,3H), 1.77 (s, 3H), 1.50 (s, 3H), 1.35 (s, 3H); HRMS (ESI) m/z calcd forC₃₃H₄₀N₃O₅S (M+H)⁺ 590.2689, found 590.2676; Anal. Calcd forC₃₃H₃₉N₃O₅S.0.3 H₂O: C, 66.60; H, 6.71; N, 7.06. Found: C, 66.65; H,6.69; N, 7.05.

EXAMPLE B44N-{(1S,2S)-1-Benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-2-methyl-nicotinamide

White solid: ¹H NMR (DMSO-d₆) δ 8.53-8.33 (m, 2H), 7.47 (d, J=7.82, 1H),7.38-7.10 (m, 12H), 5.62 (d, J=7.94, 1H), 5.18 (dd, J=9.6, 7.6, 2H),4.43-4.37 (m, 3H), 4.17 (dd, J=7.81, 6.99, 1H), 2.87-2.67 (m, 2H), 2.28(s, 3H), 2.21(s, 3H), 1.49 (s 3H), 1.34 (s, 3H); Anal. (C₃₁H₃₆N₄O₄S.1.0H₂O.1.0 MeCN) calculated C (63.95), H (6.67), N (11.30), found C(63.94), H (6.75), N (11.26). HRMS (ESI) m/z calcd for 561.2544, found561.2556.

EXAMPLE B45 Pyridine-2-carboxylicacid{(1S,2S)-1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

White solid: ¹H NMR (DMSO-d₆) δ 8.89 (d, J=7.86,), 8.66 (d, J=4.2, 1H),8.39 (t, J=6.54, 1H), 7.89 (m 2H), 7.32-7.12 (m, 9H), 5.68 (d, J=7.28,1H), 5.03 (dd J=9.7, 8.3, 2H), 4.56(m 3H), 4.40 (d, J=7.5, 1H), 4.35 (d,J=7.5, 1H), 4.21 (d, J=6.7, 1H), 2.87-2.67 (m, 2H), 2.25 (s 3H), 1.49(s, 3H), 1.34 (s, 3H); Anal. (C₃₀H₃₄N₄O₄S.0.1 H₂O.0.1 EtOAc) calculatedC (65.52), H (6.33), N (10.05), found C (65.78), H (6.69), N (9.66).HRMS (ESI) m/z calcd for 547.2380, found 547.2373.

EXAMPLE B46 Pyridine-2-5-hydroxy-carboxylicacid{(1S,2S)-1-benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-amide

White solid: ¹H NMR (DMSO-d₆) δ 8.89 (d, J=7.9, 1), 8.66 (d, J=4.2, 1H),8.39 (t, J=6.54, 1H), 7.89 (m 2H), 7.32-7.12 (m, 9H), 5.68 (d, J=7.2,1H), 5.03 (dd J=9.7, 8.3, 2H), 4.56(m 3H), 4.40 (d, J=7.5, 1H), 4.35 (d,J=7.5, 1H), 4.21 (d, J=6.7, 1H), 2.87-2.67 (m, 2H), 2.25 (s 3H), 1.49(s, 3H), 1.34 (s, 3H); Anal. (C₃₀H₃₄N₄O₅S0.5 H₂O.0.5 EtOAc) calculated C(62.29), H (6.42), N (9.91), found C (62.53), H (6.84), N (10.10). HRMS(ESI) m/z calcd for 563.2325, found 563.2328.

EXAMPLE B47N-{(1S,2S)-1-Benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-nicotinamide

White solid ¹H NMR (DMSO-d₆) δ 8.89 (d, J=7.9, 1H), 8.66 (d, J=4.2, 1H),8.39 (t, J=6.54, 1H), 7.89 (m 2H), 7.32-7.12 (m, 9H), 5.68 (d, J=7.3,1H), 5.03 (dd J=9.7, 8.3, 2H), 4.56(m 3H), 4.40 (d, J=7.5, 1H), 4.35 (d,J=7.5,1H), 4.21 (d, J=6.7,1H), 2.87-2.67 (m, 2H), 2.25 (s 3H), 1.49 (s,3H), 1.34 (s, 3H); Anal. (C₃₀H₃₄N₄O₄S.0.5 H₂O.0.5 MeCN) calculated C(64.61), H (6.39), N (10.94), found C (65.02), H (6.58), N (10.90). HRMS(ESI) m/z calcd for 547.2372, found 547.2379.

EXAMPLE B48N-{(1S,2S)-1-Benzyl-3-[5,5-dimethyl-4-(2-methyl-benzylcarbamoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-nicotinamide

White solid: ¹H NMR (DMSO-d₆) δ 8.89 (d, J=7.9, 1H), 8.66 (d, J=4.2,1H), 8.39 (t, J=6.54, 1H), 7.89 (m 2H), 7.32-7.12 (m, 9H), 5.68 (d,J=7.28, 1H), 5.03 (dd J=9.7, 8.3, 2H), 4.56(m, 3H), 4.40 (d, J=7.5, 1H),4.35 (d, J=7.5, 1H), 4.21 (d, J=6.7, 1H), 2.87-2.67 (m, 2H), 2.25 (s3H), 1.49 (s, 3H), 1.34 (s, 3H); Anal. (C₃₀H₃₄N₄O₅S.1.3 H₂O) calculatedC (61.42), H (6.32), N (9.49), found C (61.64), H (6.17), N (9.12). HRMS(ESI) m/z calcd for 563.2326, found 563.2328.

EXAMPLE B49N-[(1S,2S)-3-(4-Allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl)-1-benzyl-2-hydroxy-3-oxo-propyl]-2-methyl-nicotinamide

White solid: ¹H NMR (DMSO-d₆) δ 8.58 (m, 1H), 8.29 (d, J=7.54, 1H), 7.78(d, J=7.88, 2H), 7.32-7.12 (m, 7H), 5.78 (m, 1H), 5.18 (ddJ=9.7, 8.3,2H), 4.56(m, 3H), 4.40 (m, 4H), 2.87-2.67 (m, 2H), 2.25 (s 3H), 1.49 (s,3H), 1.34 (s, 3H); Anal. (C₂₆H₃₂N₄O₄S.0.5 H₂O.0.5 TFA) calculated C(57.68), H (6.66), N (8.31), found C (57.66), H (6.18), N (8.77). HRMS(ESI) m/z calcd for 497.2232, found 497.2223.

The synthesis of compounds with the general structure 24 is as follows.The boc-protected carboxylic acids 20a-f are coupled to the requisiteamines 2 to yield amino amides 23 using a two step process. The processincludes treatment of 20 with 2 in the presence of either diphenylchlorophosphate or EDCI, followed by exposure to HCl or methane sulfonicacid. Final compounds 24 are obtained by a DCC-mediated coupling of 23and 4 followed by deprotection of the P2 phenol. Final compounds werepurified either by flash chromatography or preparative HPLC.

The synthesis of compounds of the general structure 31 (where P2 is not2-methyl-3-hydroxy benzamide) is as follows. Amino amides of the generalstructure 23 were coupled to the Boc-acid intermediate 15 using DCCcoupling conditions. The resulting intermediate 29 was deprotected underacidic conditions to yield amine of the general structure 30. Finalcompounds were obtained by modification of amine 30 by methods describedin General Methods B section to give P2 amides and ureas.

Methods Used for Synthesis of Compounds with P1 Variations.

EDCI coupling—To a solution of acid, amine and HOBT in CH₂Cl₂ was addedEDCI and the solution stirred overnight at room temperature. Thesolution was concentrated in vacuo and the residue dissolved in ethylacetate and a small portion of water. The solution was washed withsaturated NH₄Cl (2×), saturated NaHCO₃ (2×), brine (1×), dried withMgSO₄ and concentrated in vacuo. The crude used without furtherpurification unless otherwise noted.

DCC coupling—A solution of acid, amine and HOBT was prepared in ethylacetate. To the solution was then added DCC in an EtOAc solution at 0°C. and the mixture was stirred overnight at room temperature. Themixture was filtered and the filtrate was concentrated in vacuo. Theresidue dissolved in ethyl acetate washed with saturated NH₄Cl (1×),saturated NaHCO₃ (1×), brine (1×), dried over Na₂SO₄ and concentrated invacuo. The crude was used without further purification unless otherwisenoted.

4N HCl Boc deprotection—To a solution of Boc-amine in dioxane was added4N HCl solution in dioxane and the solution stirred overnight at roomtemperature. The solution was poured into saturated NaHCO₃ and theproduct was extracted into ethyl acetate. The organic solution waswashed with brine, dried over Na₂SO₄ and concentrated in vacuo. Thecrude was used without further purification unless otherwise noted.

MeSO₃H Boc deprotection—To a solution of Boc-amine in ethyl acetate at0° C. was added methane sulfonic acid and the solution stirred 3-6 h atroom temperature. The solution was cooled to 0° C. and sufficientsaturated NaHCO₃ was added to quench the acid. The solution was dilutedwith ethyl acetate, washed with saturated NaHCO₃ and brine, dried overNa₂SO₄ and concentrated in vacuo. The crude used without furtherpurification unless otherwise noted.

KCN Phenolic acetate deprotection—A solution of phenolic acetate and KCNin ethanol was heated at 50° C. overnight. The solution was concentratedin vacuo. The residue was purified by flash chromatography eluted with 0to 5% methanol in CH₂Cl₂ unless otherwise noted.

NaOMe/MeOH Phenolic acetate deprotection—0.5 N NaOCH₃/MeOH Phenolicacetate deprotection—A solution of phenolic acetate in EtOAc andmethanol was cooled to 0° C. in an ice bath. 0.5 N NaOCH₃/MeOH was thenadded dropwise and then stirred at 0° C. for 1.5-2 hrs followingaddition. Additional EtOAc was then added, the 0.15 N HCl (4.5 eq.)added dropwise. The phases were separated and organic phase washed with2.5% Na₂CO₃ aqueous solution, then with 0.1 N HCl/brine (2:1), followedwith brine, dried with MgSO₄ and concentrated in vacuo. The resultingresidue subjected to flash silica gel chromatography to afford thedesired product unless otherwise noted.

HCl/MeOH Phenolic acetate deprotection—To a solution of phenolic acetatein methanol was added 4N HCl in dioxane and the solution stirred at roomtemperature ca. 4 h. The solution was concentrated in vacuo. The residuewas purified by flash chromatography eluted with 0 to 5% methanol inCH₂Cl₂ unless otherwise noted.

Source of Boc-carboxylic Acids 20a-f

Boc-acids 20a and 20b were prepared following the procedure of Demange,L.; Ménez, A.; Dugave, C. Tet. Lett. 1998, 39, 1169.

Boc-acids 20c, 20d, 20e and 20f were prepared following the procedure ofKaranewsky, D.; et al. J. Med. Chem. 1990, 33, 1459.

Specific Method C

EXAMPLE C1(S)-4,4-Difluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

The title compound was prepared according to general methods using thecorresponding Boc-protected pyrrolidinic acid (0.96 g, 3.8 mmol),o-methylbenzyl amine (0.57 mL, 4.6 mmol), HOBT (0.62 g, 4.6 mmol), EDCI(0.88 g, 4.6 mmol), CH₂Cl₂ (50 mL). To give the crude Boc-amide (MS-APCI(m/z+): 355, 255) (1.35 g, 3.8 mmol). The Boc was removed using thegeneral 4N HCl Boc deprotection. 4N HCl in 1,4-dioxane (5 mL),1,4-dioxane (5 mL). The result was amino amide of general structure 23.Isolated yield: 0.79 g (71%, 2 steps). ¹H NMR (400 MHz, DMSO-d₆): δ 9.02(t, 1H), 7.24-7.14 (m, 4H), 4.55 (t, 1H), 4.35 (dd, 1H), 4.30 (dd, 1H),3.73 (m, 2H), 2.94 (m, 2H), 2.52 (m, 1H), 2.27 (s, 3H); ¹⁹F NMR (376MHz, DMSO-d₆): δ−95.3 (dq, J=235, 15 Hz, 1F), −96.5 (dq, J=235, 12 Hz,1F); MS-APCI (m/z+): 255.

Amino amide 23 (100 mg, 0.34 mmol) was coupled to carboxylic acid 4 (140mg, 0.38 mmol) using the general DCC coupling method outlined above.HOBT (51 mg, 0.38 mmol), DCC (78 mg, 0.38 mmol), TEA (50 μL, 0.36 mmol),CH₂Cl₂ (10 mL). The crude was purified by chromatography eluted with 10%acetone in CH₂Cl₂. Isolated yield: 0.13 g (63%). MS-APCI (m/z+): 608.This material was subjected to the general KCN phenolic acetatedeprotection conditions (130 mg, 0.21 mmol), KCN (1 mg, 15 μmol),ethanol (10 mL). The crude was precipitated from diethyl ether and ethylacetate with hexanes at −78° C. Isolated yield: 0.10 g (84%). ¹H NMR(400 MHz, DMSO-d₆): δ 9.37 (s, 1H), 8.36 (t, 1 H), 8.16 (d, 1H),7.32-7.09 (m, 9H), 6.93 (t, 1H), 6.76 (d, 1H), 6.54 (d, 1H), 5.49 (d,1H), 4.66 (dd, 1H), 4.34-4.15 (m, 6H), 2.85-2.67 (m, 3H), 2.40 (m, 1H),2.22 (s, 3H), 1.79 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ−98.7 (m, 2F);MS-APCI (m/z+): 566; HPLC Purity: 100%; Rf (min.) 19.01; Anal.C₃₁H₃₃N₃O₅F₂.0.3 H₂O C, H, N calcd: C65.21, H5.93, N7.36; found: C65.11,H5.90, N7.17.

EXAMPLE C2(2S,4R)-4-Fluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

Isolated material was subjected to flash silica gel chromatography,eluting with EtOAc/hexanes (50/50) then with EtOAc EtOAc/hexanes (4:1)to afford the title compound. ¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (s, 1H),8.46 (t, 1 H), 8.21 (d, 1H), 7.34 (d, 2H), 7.26 (d, 2H), 7.21 (t, 2H),7.15-7.07 (m, 3H), 6.94 (t, 1H), 6.76 (d, 1H), 6.56 (d, 1H), 5.51+5.38(bs+bs, 1H), 5.06 (d, 1H), 4.58 (t, 1H), 4.45 (dd, 1H), 4.35-4.27 (m,2H), 4.21-4.09 (m, 3H), 3.94-3.91+3.84-3.81 (M+m, 1H), 2.69 (d, 2H),2.23 (s, 3H), 2.19-2.01 (m, 1H), 1.83 (s, 3H); MS-APCI (m/z+): 548;HPLC: Rf(min.) 18.72; Purity: 96%. Anal. C₃₁H₃₄N₃O₅F.0.3 H₂O calcd:67.33, 6.31, 7.60, found: 67.37, 6.25, 7.35.

EXAMPLE C3(2S,4S)-4-Fluoro-1-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-pyrrolidine-2-carboxylicacid 2-methyl-benzylamide

Isolated material was subjected to flash silica gel chromatography,eluting with EtOAc/hexanes (50/50) then with EtOAc to afford the titlecompound. ¹H NMR (400 MHz, DMSO-d₆): δ 9.37 (s, 1H), 8.21 (d, 1H), 7.96(t, 1 H), 7.29 (d, 2H), 7.23 (t, 2H), 7.18-7.13 (m, 2H), 7.10-7.04 (m,3H), 6.90 (t, 1H), 6.75 (d, 1H), 6.52 (d, 1H), 5.55 (d, 1H), 5.45+5.32(bs+bs, 1H), 4.54 (d, 1H), 4.42-4.36 (m, 1H), 4.29-4.40 (m, 5H), 2.98(t, 1H), 2.73 (t, 1H), 2.32-2.21 (m, 2H), 2.19 (s, 3H), 1.78 (s, 3H);MS-APCI (m/z+): 548; HPLC: Rf(min.) 18.21; Purity: 99%; Anal.C₃₁H₃₄N₃O₅F.0.5 H₂O calcd: 66.89, 6.34, 7.55, found: 66.85, 6.22, 7.41.

EXAMPLE C4(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-oxazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.80 (dd, J=8.8, 4.8, 1H),8.30 (t, J=5.5, 1H), 8.12 (d, J=8.6, 1H), 7.30-7.13 (m, 9H), 6.96 (t,J=7.9, 1H), 6.76 (d, J=7.9, 1H), 6.55 (d, J=7.2, 1H), 5.74 (d, J=8.8,1H), 5.31 (d, J=3.8, 1H), 5.23 (d, J=4.2, 1H), 4.49 (dd, J=6.6, 6.5,1H), 4.33-4.11 (m, 5H), 2.94-2.68 (m, 2H), 2.24 (s, 3H), 1.78 (s, 3H);HRMS (ESI) m z calcd for C₃₀H₃₄N₃O₆ (M+H)⁺ 532.2448, found 532.2450.

EXAMPLE C5(4S,5R)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5-methyl-oxazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.38 (s, 1H), 8.51 (t, J=6.0, 1H), 8.15(d, J=8.4, 1H), 7.33-7.13 (m, 9H), 6.96 (t, J=7.7, 1H), 6.79 (d, J=8.2,1H), 6.58 (d, J=7.3, 1H), 5.69 (d, J=5.7, 1H), 5.50 (d, J=4.6, 1H), 5.10(d, J=4.8, 1H), 4.39-4.22 (m, 4H), 4.11-4.01 (m, 2H), 2.90 (m, 1H), 2.74(m, 1H), 2.27 (s, 3H), 1.82 (s, 3H), 1.37 (d, J=5.9, 1H); HRMS (ESI) m/zcalcd for C₃₁H₃₆N₃O₆ (M+H)⁺ 546.2604, found 546.2595.

EXAMPLE C6(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.32 (t, J=5.8, 1H), 8.11(J=9.0, 1H), 7.31-7.10 (m, 9H), 6.93 (t, J=7.9, 1H), 6.76 (d, J=8.1,1H), 6.55 (d, J=6.5, 5 1H), 5.73 (d, J=4.0, 1H), 5.46 (d, J=4.1, 1H),5.23 (d, J=3.9, 1H), 4.39-4.32 (m, 2H), 4.18 (m, 3H), 2.92 (m, 1H), 2.69(m, 1H), 2.27 (s, 3H), 1.81 (s, 3H), 1.28 (s, 3H), 1.18 (s, 3H); HRMS(ESI) m/z calcd for C₃₂H₃₈N₃O₆ (M+H)⁺ 560.2761, found 560.2759; Anal.Calcd for C₃₂H₃₇N₃O₆.0.5 H₂O: C, 67.59; H, 6.74; N, 7.39. Found: C,67.74; H, 6.75; N, 7.16.

EXAMPLE C7(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid propylamide

¹H NMR (DMSO-d₆) δ 9.37 (s, 1H), 8.12 (d, J=9.3, 1H), 7.93 (t, J=5.6,1H), 7.34-7.18 (m, 5H), 6.96 (t, J=8.1, 1H), 6.79 (d, J=8.1, 1H), 6.56(d, J=7.1, 1H), 5.73 (d, J=6.2, 1H), 5.44 (d, J=4.0, 1H), 5.24 (d,J=3.8, 1H), 4.36 (m, 1H), 4.18 (m, 1H), 4.11 (s, 1H), 3.10-2.92 (m, 3H),2.75-2.66 (m, 1H), 1.80 (s, 3H), 1.46-1.39 (m, 2H), 1.31 (s, 3H), 1.22(s, 3H), 0.86 (t, J=7.2, 3H); HRMS (ESI) m/z calcd for C₂₇H₃₆N₃O₆ (M+H)⁺498.2604, found 498.2590.

EXAMPLE C8(4S,5S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5-methyl-oxazolidine-4-carboxylicacid 2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.26 (t, J=5.5, 1H), 8.09(d, J=8.8, 1H), 7.30-7.08 (m, 9H), 6.93 (t, J=7.7, 1H), 6.76 (d, J=7.9,1H), 6.56 (d, J=7.5, 1H), 5.72 (d, J=6.4, 1H), 5.55 (d, J=3.7, 1H), 5.08(d, J=3.8, 1H), 4.40-4.33 (m, 3H), 4.26-4.11 (m, 3H), 3.10-2.89 (m, 1H),2.78-2.67 (m, 1H), 2.26 (s, 3H), 1.78 (s, 3H), 1.15 (d, J=6.2, 3H); HRMS(ESI) m/z calcd for C₃₁H₃₆N₃O₆ (M+H)⁺ 546.2604, found 546.2592.

EXAMPLE C9(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid 5-fluoro-2-methyl-benzylamide

White solid; ¹H NMR (DMSO-d₆) δ 9.35 (s, 1H), 8.41 (t, J=5.6, 1H), 8.12(d, J=8.9, 1H), 7.28-7.08 (m, 8H), 6.95-6.90 (m, 1H), 6.76 (d, J=8.1,1H), 6.55 (d, J=7.2, 1H), 5.78 (d, J=6. 1, 1H), 5.47 (d, J=3.8, 1H),5.24 (d, J=3.8, 1H), 4.40-4.25 (m, 2H), 4.20-4.10 (m, 3H), 3.00-2.60 (m,2H), 2.22 (s, 3H), 1.77 (s, 3H), 1.30 (s, 3H), 1.19 (s, 3H); Anal. Calcdfor C₃₂H₃₆N₃O₆F: C, 66.54; H, 6.28; N, 7.27. Found: C, 66.37; H, 6.20;N, 7.21.

EXAMPLE C10(S)-3-((2S,3S)-2-Hydroxy-3-{[1-(3-hydroxy-2-methyl-phenyl)-methanoyl]-amino}-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid cyanomethyl-amide

White solid; ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.72 (t, J=5.3, 1H), 8.11(d, J=9.0, 1H), 7.29-7.16 (m, 5H), 6.94 (t, J=7.7, 1H), 6.76 (d, J=8.1,1H), 6.50 (d, J=7.5, 1H), 5.85 (d, J=6.0, 1H), 5.49 (d, J=4.0, 1H), 5.23(d, J=3.9, 1H), 4.35 (m, 1H), 4.18-4.12 (m, 3H), 4.11 (s, 1H), 2.92 (m,1H), 2.70 (m, 1H), 1.76 (s, 3H), 1.29 (s, 3H), 1.19 (s, 3H); HRMS (ESI)m/z calcd for C₂₆H₃₁N₄O₆ (M+H)⁺ 495.2244, found 495.2239.

EXAMPLE C11(S)-3-((2S,3S)-3-{[1-(3-Fluoro-2-methyl-phenyl)-methanoyl]-amino}-2-hydroxy-4-phenyl-butanoyl)-5,5-dimethyl-oxazolidine-4-carboxylicacid 2-methyl-benzylamide

¹H NMR (DMSO-d₆) δ 8.34 (m, 2H), 7.30-7.13 (m, 11H), 6.95 (d, J=7.1,1H), 5.82 (d, J=6.4, 1H), 5.45 (d, J=3.9, 1H), 5.23 (d, J=4.0, 1H),4.38-4.31 (m, 2H), 4.18-4.15 (m, 3H), 2.96 (m, 1H), 2.67 (m, 1H), 2.26(s, 3H), 1.87 (s, 3H), 1.28 (s, 3H), 1.18 (s, 3H); HRMS (ESI) m/z calcdfor C₃₂H₃₇N₃O₅F (M+H)⁺ 562.2717, found 562.2713.

The synthesis of compounds with the general structure 27 is as follows.The boc-protected thiazolidine carboxylic acid 1 is converted toamino-ketones 26 with requisite grignard reagents 25 in the presence ofoxalyl chloride. Final compounds 27 are obtained by a DCC-mediatedcoupling of 26 and 4 followed by deprotection of the P2 phenol. Finalcompounds were purified either by flash chromatography or preparativeHPLC.

Specific Method D

EXAMPLE D1N-[(1S,2S)-1-Benzyl-3-((R)-5,5-dimethyl-4-pent-4-enoyl-thiazolidin-3-yl)-2-hydroxy-3-oxo-propyl]-3-hydroxy-2-methyl-benzamide

The title compound was prepared as follows.(R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester 1(1.0 g, 3.80 mmol) was dissolved in benzene (10 mL) and cooled to 0° C.with magnetic stirring. Two drops of DMF were added followed by a dropwise addition of oxalyl chloride (0.33 mL, 3.80 mmol). When gasevolution ceased, the solution was concentrated to a yellow/red residue.The material was dissolved in dry THF (10 mL) and cooled to −78° C. withmagnetic stirring. The grignard reagent, 3-butenylmagnesium bromide (7.7mL, 3.80 mmol) was added dropwise over 10 min. The result was stirred at−78° C. for 1 h then at −55° C. for 30 min. The reaction was quenched at−55° C. with sat NH₄Cl soln.(3 mL) and then poured into H₂O (50 mL). Themixture was extracted with EtOAc (2×50 mL). The combined organics werewashed with brine (1×100 mL), dried over Na₂SO₄, filtered, andconcentrated. The result was the amino ketone 26 that was sufficientlypure to use in the subsequent step. The clear oil 26 (0.24 g, 1. 15mmol) was dissolved in EtOAc (10 mL). AMB-AHPBA 4 (0.40 g, 1.09 mmol)was added followed by HOBt (0.15 g, 1.09 mmol). The mixture was stirredat room temperature 1 h, then cooled to 0° C. DCC (0.24 g, 1.15 mmol)was slowly added as solution in EtOAc (6 mL). The mixture was warmed toroom temperature and stirred overnight. The mixture was filtered and thefiltrate was washed with 1N HCl (10 mL), saturated NaHCO₃ (10 mL), brine(10 mL), dried over Na₂SO₄ and concentrated to give a crude white solid(contaminated with DCU). The DCU was removed by flash chromatography(30% to 50% EtOAc in hexanes) to provide a white solid, which wasdissolved in MeOH (2 mL) and treated with 4N HCl in 1,4-dioxane (0.26mL, 1.1 mmol). The reaction was stirred at room temperature overnightthen partitioned between 1N HCl (10 mL) and EtOAc (10 mL). The organiclayer was washed with saturated sat. NaHCO₃ (1×25 mL) dried over Na₂SO₄,filtered, and concentrated to a residue which was purified by flashchromatography (60% EtOAc in hexanes) to provide the title compound as awhite amorphous solid: ¹H NMR (DMSO-d₆) δ 9.36 (s, 1H), 8.23 (d, J=8.1,1H), 7.35-7.14 (m, 5H), 6.96 (t, J=7.5, 1H), 6.78 (d, J=8.2, 1H), 6.52(d, J=7.5, 1H), 5.81-5.69 (m. 2H), 5.32 (d, J=9.7, 1H), 5.11-5.91 (m,3H), 4.40 (m, 3H), 2.89-2.61 (m, 4H), 2.37-2.14 (m, 2H), 1.81 (s, 3H),1.55 (s, 3H), 1.30 (s, 3H); Anal. Calcd for C₂₈H₃₄N₂O₅S: C, 65.86; H,6.71; N, 5.49. Found: C, 65.52; H, 6.55; N, 5.81.

The following examples were synthesized using the specific methodoutlined above using the appropriate grignard reagent for the desiredcompound.

EXAMPLE D2N-{1-Benzyl-3-[5,5-dimethyl-4-(4,4,4-trifluoro-butanoyl)-thiazolidin-3-yl]-2-hydroxy-3-oxo-propyl}-3-hydroxy-2-methyl-benzamide

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.16 (d, 1H, J=8.6), 7.29-6.49 (m, 8H),5.88 (d, 1H, J=6.1), 5.33 (d, 1H, J=9.5), 5.10 (d, 1H, J=9.5), 4.56 (sbr, 3H), 2.98-2.57 (m, 6H), 1.74 (s, 3H), 1.55 (s, 3H), 1.30 (s, 3H);HRMS (ESI) m/z calcd for C₂₇H₃₂N₂O₅SF₃ (M+H)⁺ 553.1984, found 553.1984;Anal. Calcd for C₂₇H₃₁N₂O₅SF₃.0.5H₂O: C, 58.59; H, 5.66; N, 5.06; S,5.79. Found: C, 58.96; H, 6.02; N, 5.58; S, 5.33.

EXAMPLE D3N-{1-Benzyl-2-hydroxy-3-[4-(4-methoxy-butanoyl)-5,5-dimethyl-thiazolidin-3-yl]-3-oxo-propyl}-3-hydroxy-2-methyl-benzamide

¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.18 (d, 1H, J=8.2), 7.32-6.51 (m, 8H),5.56 (d, 1H, J=7.8), 5.26 (d, 1H, J=9.5), 5.08 (d, 1H, J=9.5), 4.45-4.38(m, 2H), 4.36 (s, 1H), 3.15 (s, 3H), 2.93-2.61 (m, 2H), 1.87-1.00 (m,6H), 1.80 (s, 3H), 1.55 (s, 3H), 1.36 (s, 3H); HRMS (ESI) m/z calcd forC₂₈H₃₇N₂O₆S (M+H)⁺ 529.2165, found 529.2372; Anal. Calcd forC₂₈H₃₆N₂O₆S.0.5H₂O: C, 62.55; H, 6.94; N, 5.21; S, 5.96. Found: C,62.89; H, 7.32; N, 5.96; S, 5.59.

EXAMPLE D4 (R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2,5-dimethyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

White solid: ¹H NMR (DMSO-d₆) δ 9.23 (s, 1H), 8.09 (m, 2H), 7.35-7.17(m, 5H), 6.60 (s, 1H), 6.37 (s, 1H), 5.82-5.68 (m, 1H), 5.41 (br s, 1H),5.20 (dd, 1H, J=1.6, 17.2),5.11 (d, 1H,J=9.2),5.02 (dd, 1H,J=1.5,10.2),5.00 (d, 1H,J=9.1), 4.46-4.37 (m, 3H), 3.79 (ddd, 1H, J=5.3, 5.5,15.9), 3.63 (ddd, 1H, J=5.4, 5.3, 15.9), 2.82 (dd, 1H, J=0.3, 13.9),2.71 (dd, 1H, J=10.7, 13.6), 2.16 (s, 3H), 1.76 (s, 3H), 1.51 (s, 3H),1.36 (s, 3H); HRMS (ESI) m/z calcd for C₂₈H₃₆N₃O₅S (M+H)⁺ 526.6670,found 526.2376; Anal. Calcd for C₂₈H₃₅N₃O₅S.0.3 H₂O: C, 63.32; H, 6.76;N, 7.91, Found: C, 63.35; H, 6.70; N, 7.71.

Combinatorial Chemistry Approach to HIV Protease P2′ Inhibitors

General Method E

The combinatorial building block, 8, is prepared using the followingmethod. The boc-protected thiazolidine carboxylic acid, 1, is treatedwith allyl bromide in the presence of NaHCO₃ to yield the boc-protectedthiazolidine allyl ester, 2. Deprotection of boc-protected allyl ester,2, with HCl (g) in EtOAc gives the HCl salt of the thiazolidine allylester amine, 3, which is treated with TEA and coupled to 4 in thepresence of HOBT and DCC to give the building block precursor, 5.Deprotection of the building block, 5, with 4N HCl yields the phenol, 6.Loading the building block, 6, on to activated cross-linked tritylchloride polystyrene beads, 7, was accomplished in the following manner.The polystyrene cross-linked trityl alcohol was activated to the tritylchloride, 7, by treatment with 20% acetyl chloride in anhydrous CH₂Cl₂at room temperature. The trityl chloride beads were combined with thephenol 6 in the presence of Hunig's base in anhydrous CH₂Cl₂ to yieldthe substrate loaded polystyrene beads 8. Intermediates were purifiedeither by flash chromatography or preparative HPLC.

The synthesis of the HIV protease combinatorial library was carried outin the following fashion. The allyl ester was removed by treatment withPd[PPh₃]₄ and NMM in anhydrous THF to give carboxylate 9, which wastreated with pentafluorophenol, pentafluorophenol trifluoromethylacetate and pyridine in DMF to yield the pentafluoro ester, 10. Thepentafluoro ester 10 was treated with various primary amines in a96-well plate format to give amides 12. The final products were cleavedfrom the polystyrene crowns with TFA to give products 13. Each productwas analyzed by LCMS and HPLC. The following table typifies compoundssynthesized by this combinatorial method. TABLE 1 Expected Mass Observed% P2′ (LCMS) Mass Inhibition

529 552(Na⁺) 38

528 529(MH⁺) 4

591 614(Na⁺) 18

555 578(Na⁺) 19

635 658(Na⁺) 5

656 656(MH⁺) 8

575 598(Na⁺) 86

541 564(Na⁺) 63

529 552(Na⁺) 49

The solid phase combinatorial synthesis of HIV protease inhibitors wasperformed using the IRORI Directed Sorting Technology. Commercial4-formyl-3-methoxyphenoxymethyl polystyrene resin 1a (PS-MB-CHO,Argonaut Technologies) or 4-formyl-3,5-dimethoxyphenoxymethylpolystyrene resin 1b (PL-FDMP resin, Polymer Laboratories) was loadedinto individual Minikans.

Step A. Reductive Amination With P₂′ Amines

To separate flasks containing sorted MiniKans was added DCM (3mL/MiniKan). The appropriate primary P₂′ amine (3 eq), sodiumtriacetoxyborohydride (5 eq), and acetic acid (3 eq) were added, and themixtures were placed under argon, agitated with periodic venting at roomtemperature for 1-2 hours, and allowed to react overnight. For resin 1a,the filtrates were poured off and the MiniKans were washed with DCM,MeOH (2×), DCM (2×), Et₃N/DCM (1:3, 3×), DCM (2×), MeOH (3×), and DCM(4×). For resin 1b, a washing sequence of DCM, MeOH (2×), DCM (2×),Et₃N/DCM (1:3, 3×), DCM (2×), DMF, 1M NaOH/DMF (1:5, 3×), DMF (3×), MeOH(3×), and DCM (3×) was used. The MiniKans were dried under vacuum andtaken on in Step B.

Step B. Peptide Coupling With P₁′ Amino Acids

To separate flasks containing the sorted MiniKans was added DMF (3mL/MiniKan). The appropriate FMOC-protected amino acid (2.5 eq) and1-hydroxy-7-azabenzotriazole (HOAT) (3 eq) were added and mixed untildissolved, and 1,3-diisopropylcarbodiimide (DIC) (3 eq) was added. Thecontainers were placed under argon and agitated at room temperatureovernight. The filtrates were poured off, and the MiniKans were washedwith DMF (3×), MeOH (3×), DCM (2×), and DMF (2×). The MiniKans weretaken directly on to Step C.

Step C. FMOC Deprotection

A container of MiniKans in DMF and piperidine (25%) with a totalreaction volume of 3 mL/MiniKan was agitated under argon at roomtemperature for 45 minutes. The filtrate was removed, and the reactionprocedure was repeated. The MiniKans were filtered and washed with DMF(3×), MeOH (2×), DCM (3×), and DMF, and taken directly on to Step D.

Step D. Peptide Coupling With FMOC-APNS

FMOC-Allophenylnorstatine (APNS) (3 eq) was added to the flask ofMiniKans in DMF (3 mL/MiniKan). After dissolution, HOAT (3.5 eq) and DIC(3.5 eq) were added. The mixture was placed under argon and agitated atroom temperature overnight. The reaction was filtered and the MiniKanswere washed with DMF (3×), MeOH (3×), DCM (3×), and DMF. FMOCdeprotection was carried out as in Step C, and the MiniKans were washedwith DMF (3×), MeOH (2×), DCM (3×), dried under vacuum and taken on toStep E or F.

Step E. Peptide Coupling With P₂ Acids

To separate flasks containing the sorted MiniKans in DMF (3 mL/MiniKan)was added the appropriate P₂ acid (3 eq), HOBT hydrate (4 eq), and(3-(dimethylamino)propyl)ethylcarbodiimide hydrochloride (EDAC) (3.5eq). The reaction was agitated under argon at room temperature for 3hours. After filtration, the MiniKans were washed with DMF (3×), MeOH(3×), and DCM (3×), dried under vacuum, and taken on to Step G.

Step F. Cleavage and Processing Of The HIV Analogs

The individual MinKans were sorted into cleavage racks and a solution of25% TFA in DCM (3 mL/MinKan) was added. The racks were agitated for 1.5hours. The individual filtrates and DCM rinses were collected,concentrated, and purified by HPLC to provide the final compounds. TABLE2

Scheme 3 Experimental

The solid phase combinatorial synthesis of HIV protease inhibitors wasperformed using the IRORI Directed Sorting Technology. Commercial4-formyl-3-methoxyphenoxymethyl polystyrene resin 1a (PS-MB-CHO,Argonaut Technologies) or 4-formyl-3,5-dimethoxyphenoxymethylpolystyrene resin 1b (PL-FDMP resin, Polymer Laboratories) was loadedinto individual Minikans.

Step A. Reductive Amination With P₂′ Amines

To separate flasks containing sorted MiniKans was added DCM (3mL/MiniKan). The appropriate primary P₂′ amine (3 eq), sodiumtriacetoxyborohydride (5 eq), and acetic acid (3 eq) were added, and themixtures were placed under argon, agitated with periodic venting at roomtemperature for 1-2 hours, and allowed to react overnight. For resin 1a,the filtrates were poured off and the MiniKans were washed with DCM,MeOH (2×), DCM (2×), Et₃N/DCM (1:3, 3×), DCM (2×), MeOH (3×), and DCM(4×). For resin 1b, a washing sequence of DCM, MeOH (2×), DCM (2×),Et₃N/DCM (1:3, 3×), DCM (2×), DMF, 1M NaOH/DMF (1:5, 3×), DMF (3×), MeOH(3×), and DCM (3×) was used. The MiniKans were dried under vacuum andtaken on in Step B.

Step B. Peptide Coupling With P₁′ Amino Acids

To separate flasks containing the sorted MiniKans was added DMF (3mL/MiniKan). The appropriate FMOC-protected amino acid (2.5 eq) and1-hydroxy-7-azabenzotriazole (HOAT) (3 eq) were added and mixed untildissolved, and 1,3-diisopropylcarbodiimide (DIC) (3 eq) was added. Thecontainers were placed under argon and agitated at room temperatureovernight. The filtrates were poured off, and the MiniKans were washedwith DMF (3×), MeOH (3×), DCM (2×), and DMF (2×). The MiniKans weretaken directly on to Step C.

Step C. FMOC Deprotection

A container of MiniKans in DMF and piperidine (25%) with a totalreaction volume of 3 mL/MiniKan was agitated under argon at roomtemperature for 45 minutes. The filtrate was removed, and the reactionprocedure was repeated. The MiniKans were filtered and washed with DMF(3×), MeOH (2×), DCM (3×), and DMF, and taken directly on to Step D.

Step D. Peptide Coupling With FMOC-APNS

FMOC-Allophenylnorstatine (APNS) (3 eq) was added to the flask ofMiniKans in DMF (3 mL/MiniKan). After dissolution, HOAT (3.5 eq) and DIC(3.5 eq) were added. The mixture was placed under argon and agitated atroom temperature overnight. The reaction was filtered and the MiniKanswere washed with DMF (3×), MeOH (3×), DCM (3×), and DMF. FMOCdeprotection was carried out as in Step C, and the MiniKans were washedwith DMF (3×), MeOH (2×), DCM (3×), dried under vacuum and taken on toStep E or F.

Step E. Peptide Coupling With P₂ Acids

To separate flasks containing the sorted MiniKans in DMF (3 mL/MiniKan)was added the appropriate P₂ acid (3 eq), HOBT hydrate (4 eq), and(3-(dimethylamino)propyl)ethylcarbodiimide hydrochloride (EDAC) (3.5eq). The reaction was agitated under argon at room temperature for 3hours. After filtration, the MiniKans were washed with DMF (3×), MeOH(3×), and DCM (3×), dried under vacuum, and taken on to Step G.

Step F. Cleavage and Processing of the HIV Analogs

The individual MinKans were sorted into cleavage racks and a solution of25% TFA in DCM (3 mL/MinKan) was added. The racks were agitated for 1.5hours. The individual filtrates and DCM rinses were collected,concentrated, and purified by HPLC to provide the final compounds. TABLE3

EXAMPLE F1 Preparation of(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acidtert-butyl ester

(4R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butyl ester(which can be prepared according to the methods of Ikunaka, M. et al.,Tetrahedron Asymm. 2002, 13, 1201; Mimoto, T. et al., J. Med. Chem.1999, 42, 1789; and Mimoto, T. et al., European Patent Application0574135A1 (1993), 250 g; 0.957 mol) was added to an argon-purged 5-Lflask and was dissolved in EtOAc (1.25 L). The solution was cooled to 2°C. and (PhO)₂POCl (208 mL; 1.00 mol) was then added in one portion. NEt₃(280 mL; 2.01 mol) was added dropwise via addition funnel and theresulting suspension was then stirred at 0° C. Seven minutes later,allylamine (75.4 mL; 1.00 mol) was added dropwise. The ice bath wasremoved and the suspension was allowed to warm to room temperature.One-half hour later, 1 N HCl (750 mL; 0.750 mol) was added. The mixturewas transferred to a 4-L separatory funnel using EtOAc (50 mL) forrinsing. The layers were separated. The organic fraction was washed with7.2% aqueous Na₂CO₃ (2×1.25 L), and was then transferred to a 3-Ldistillation flask and was diluted with EtOAc (400 mL). The solution wasdried azeotropically and concentrated to a volume of 800 mL bydistillation of EtOAc at one atmosphere. After cooling to 25° C., theresulting clear yellowish EtOAc solution of(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acidtert-butyl ester was carried on directly into the next step. An aliquotwas removed and concentrated to give(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acidtert-butyl ester as a white crystalline solid: mp=94-98° C., ¹H NMR (300MHz, CDCl₃) δ 6.12 (br s, 1H), 5.88 (app ddt, J=10.2, 17.1, 5.6 Hz, 1H),5.28 (app dq, J=17.1, 1.5 Hz, 1H), 5.18 (app dd, J=1.2, 10.2 Hz, 1H),4.68 (s, 2H), 4.14 (br s, 1H), 3.95 (br t, J=5.4 Hz, 2H), 1.62 (s, 3H),1.49 (s, 9H), 1.46 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 170.0, 154.0,134.4, 116.9, 82.0, 73.3, 54.0, 48.7, 42.0, 30.6, 28.6, 24.6; MS (CI)m/z 301.1599 (301.1586 calcd for C₁₄H₂₅N₂O₃S, M+H⁺); elemental analysiscalcd for C₁₄H₂₄N₂O₃S: C, 55.97; H, 8.05; N, 9.32; found: C, 56.11; H,8.01; N, 9.11.

EXAMPLE F2 Preparation of (4R)-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

Methanesulfonic acid (155 mL; 2.39 mol) was added dropwise to the EtOAcsolution of (4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylicacid tert-butyl ester in a 3-L flask. After stirring at room temperatureovernight, the solution was cooled to 7° C. and H₂O (400 mL) was pouredin. The mixture was transferred to a 4-L separatory funnel [using H₂O(30 mL) for rinsing] and the layers were separated. The organic fractionwas extracted with H₂O (190 mL). The combined H₂O extracts weretransferred to a 5-L flask and were cooled to 8° C. The pH was adjustedfrom 0.4 to 9.3 using 3 N NaOH (˜1.05 L). 2-Methyltetrahydrofuran (1.55L) was poured in, followed by the addition of NaCl (150 g). The ice bathwas removed and the mixture was allowed to warm to room temperature. ThepH was readjusted to 9.0 using 3 N NaOH (˜1 mL). The mixture wastransferred to a 4-L separatory funnel, using 2-methyltetrahydrofuran(50 mL) for rinsing, and the layers were separated. The aqueous phasewas extracted with 2-methyltetrahydrofuran (950 mL). The organicextracts were vacuum-filtered through Celite directly into a 5-Ldistillation flask, using 2-methyltetrahydrofuran (200 mL) for rinsing.The solution was dried azeotropically and concentrated to a volume of1.2 L by distillation of 2-methyltetrahydrofuran at one atmosphere. Ameasured aliquot was concentrated and weighed, which showed that 161 gof (4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide waspresent in solution [84% from(4R)-5,5-dimethyl-thiazolidine-3,4-dicarboxylic acid 3-tert-butylester]. This solution was then carried on directly into the next step.The concentrated aliquot from above yielded(4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide as acrystalline solid: mp=45-47° C., ¹H NMR (300 MHz, CDCl₃) δ 6.73 (br s,1H), 5.87 (app ddt, J=10.2, 17.1, 5.7 Hz, 1H), 5.17-5.27 (m, 2H), 4.27(AB q, JAB=9.7 Hz, Av=22.5 Hz, 2H), 2.94 (app tt, J=1.5, 5.8 Hz, 2H),3.51 (s, 1H), 1.74 (s, 3H), 1.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃) δ169.7, 134.4, 116.9, 74.8,57.2,51.6, 41.9, 29.1, 27.3; MS (CI) m/z201.1063 (201.1062 calcd for C₉H₁₇N₂OS, M+H⁺); elemental analysis calcdfor C₉H₁₆N₂OS: C, 53.97; H, 8.05; N, 13.99; found: C, 53.93; H, 8.09; N,14.07.

EXAMPLE F3 Preparation of(2S,3S)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyricacid

(2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyric acid (which can be preparedaccording to the method of Pedrosa et al., Tetrahedron Asymm. 2001, 12,347; M. Shibasaki et al., Tetrahedron Lett. 1994, 35, 6123; and Ikunaka,M. et al. Tetrahedron Asymm. 2002, 13, 1201; 185 g; 948 mmol) was addedto a 5-L flask and was suspended in THF (695 mL). H₂O (695 mL) waspoured in, followed by NEt₃ (277 mL; 1990 mmol). After stirring for 45min, the solution was cooled to 6° C. A solution of acetic acid3-chlorocarbonyl-2-methyl-phenyl ester (201 g; 948 mmol) in THF (350 mL)was then added dropwise. One-half hour later, the pH was adjusted from8.7 to 2.5 with 6 N HCl (˜170 mL). Solid NaCl (46 g) was added, the icebath was then removed and the mixture was stirred vigorously whilewarming to room temperature. The mixture was transferred to 4-Lseparatory funnel, using 1:1 THF/H₂O (50 mL) for the transfer, and thelower aqueous phase was then removed. The organic fraction wastransferred to a 5-L distillation flask, and was then diluted with freshTHF (2.5 L). The solution was azeotropically dried and concentrated to avolume of 1.3 L by distillation of THF at one atmosphere. To completethe azeotropic drying, fresh THF (2.0 L) was added and the solution wasconcentrated to 1.85 L by distillation at one atmosphere and was thenheld at 55° C. n-Heptane (230 mL) was added dropwise via addition funneland the solution was then immediately seeded. After crystallization hadinitiated, additional n-heptane (95 mL) was added dropwise. Theresulting crystal slurry was stirred vigorously for 7 min. Additionaln-heptane (1.52 L) was then added as a slow stream. The crystal slurrywas then allowed to cool to room temperature slowly and stir overnight.The suspension was vacuum-filtered and the filter cake was then washedwith 1:1 THF/n-heptane (700 mL). After drying in a vacuum oven at 45-50°C., 324 g (92%) of(2S,3S)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyricacid was obtained as a crystalline solid contaminated with ˜7 mol %Et₃N.HCl: mp=189-191° C., ¹H NMR (300 MHz, DMSO-d₆) δ 12.65 (br s, 1H),3.80 (d, J=9.7 Hz, 1H), 7.16-7.30 (m, 6H), 7.07 (dd, J=1.1, 8.0 Hz, 1H),7.00 (dd, J=1.1, 7.5 Hz), 4.40-4.52 (m, 1H), 4.09 (d, J=6.0 Hz, 1H),2.92 (app dd, J=2.9, 13.9 Hz, 1H), 2.76 (app dd, J=11.4, 13.9 Hz, 1H),2.29 (s, 3H), 1.80 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆) δ 174.4, 169.3,168.1, 149.5, 139.7, 139.4, 129.5, 128.3, 127.9, 126.5, 126.3, 124.8,123.3, 73.2, 53.5, 35.4, 20.8, 12.6; MS (CI) m/z 372.1464 (372.1447calcd for C₂₀H₂₂NO₆, M+H⁺); elemental analysis calcd for C₂₀H₂₁NO₆.0.07Et₃N.HCl: C, 64.34; H, 5.86; N, 3.95; Cl, 0.70; found: C, 64.27; H,5.79; N, 3.96; Cl; 0.86.

EXAMPLE F4 Preparation of acetic acid3-{(1S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenylester

(2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyricacid (271 g; 731 mmol) was added to a 5-L flask containing a solution of(4R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide (161 g; 804mmol) in 2-methyltetrahydrofuran (1.20 L total solution), while using2-methyltetrahydrofuran (500 mL) for rinsing. HOBt.H₂O (32.6 g; 241mmol) was added, using 2-methyltetrahydrofuran (50 mL) for rinsing. Thewhite suspension was allowed to stir at room temperature for 10 min.Diisopropylcarbodiimide (119 mL; 760 mmol) was added in three portions(40 mL+40 mL+39 mL) at 30 min intervals. One hour after the final DICaddition, Celite (100 g) was added and the suspension was allowed tostir at room temperature for 3 h. The mixture was vacuum-filtered, while2-methyltetrahydrofuran (400 mL) was used to rinse over the solids andwash the resulting filter cake. The filtrate was transferred to 4-Lseparatory funnel, using 2-methyltetrahydrofuran (50 mL) for rinsing.The solution was washed with 1 N HCl (1.25 L), and then with an aqueoussolution of NaHCO₃ (27 g), NaCl (134 g) and H₂O (1.25 L). The resultingorganic phase was transferred to a 3-L distillation flask and thesolution was then reduced to a volume of 1.12 L by distillation of2-methyltetrahydrofuran at one atmosphere. The solution was then dilutedwith 2-methyltetrahydrofuran (230 mL) to bring the total volume to 1.35L. After cooling the solution to 23° C., the solution of crude aceticacid3-{(1S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenylester on directly into the next step.

EXAMPLE F5 Preparation of(4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

MeOH (330 mL) and K₂CO₃ (66.9 g; 484 mmol) were sequentially added to a2-methyltetrahydrofuran solution of crude acetic acid3-{(1S,2S)-3-[(4R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-2-hydroxy-3-oxo-propylcarbamoyl}-2-methyl-phenylester (theoretical amount: 405 g; 731 mmol) in a 3-L flask at roomtemperature. Two and a half hours later, additional K₂CO₃ (20 g; 144mmol) was added. Three hours later the reaction mixture wasvacuum-filtered on a pad of Celite, using 4:12-methyltetrahydrofuran/MeOH (330 mL) for rinsing over the solids andwashing the filter cake. The filtrate was transferred to a 6-Lseparatory funnel, using 4:1 2-methyltetrahydrofuran/MeOH (80 mL) forrinsing. The solution was diluted with i-PrOAc (1.66 L) and was thenwashed with a solution of NaCl (83.0 g) in H₂O (1.60 L). The organicfraction was washed with 0.5 N HCl (1.66 L) and then with a saturatedaqueous NaCl solution (400 mL). The resulting organic fraction wastransferred to a 4-L Erlenmeyer flask and MgSO₄ (120 g) was added. Afterstirring for 10 min, the mixture was vacuum-filtered directly into a 5-Ldistillation flask, using 2:1 i-PrOAc/2-methyltetrahydrofuran (600 mL)for rinsing the separatory funnel and Erlenmeyer flask and washing theMgSO₄. The 2-methyltetrahydrofuran was displaced by distillation at oneatmosphere with the simultaneous addition of i-PrOAc in five portions (atotal of 3.60 L was used), while maintaining a minimum pot volume of˜2.50 L. The resulting crystallizing mixture was cooled to 75° C. andwas held at this temperature for 30 min. The suspension was then allowedto slowly cool to room temperature overnight. The suspension wasvacuum-filtered, using i-PrOAc (600 mL) for transferring and washing thecrystals. After drying in a vacuum oven at 40° C., 204 g (54% from(2S,3S)-3-(3-Acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyricacid) of crystalline(4R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide was obtained. This material was recrystallized asdescribed below.

EXAMPLE F6 Recrystallization of(4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

(4R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide (193 g, 378 mmol) was added to a 5-L flask and was thensuspended in EtOAc (1.28 L). After heating the suspension to 76° C.,MeOH (68 mL) was added and the internal temperature was then reduced to70° C. n-Heptane (810 mL) was added dropwise to the solution, whilemaintaining the internal temperature at 70° C. After the n-heptaneaddition was complete, the resulting crystal suspension was held at 70°C. for 30 min, and was then allowed to slowly cool to room temperatureovernight. The suspension was vacuum-filtered, using 1.6:1EtOAc/n-heptane (500 mL) to transfer and wash the crystals. The crystalswere then dried in a vacuum oven at 45° C. to give 162 g (84% recovery)of purified(4R)-3-[(2S,3S)-2-Hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide as a white crystalline solid: mp=173-175° C., ¹H NMR(300 MHz, DMSO-d₆) displayed a ˜10:1 mixture of rotamers, major rotamerresonances δ 9.35 (s, 1H), 8.04-8.15 (m, 2H), 7.13-7.38 (m, 5H), 6.96(t, J=7.7 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H),5.71-5.87 (m, 1H), 5.45 (br d, J=6.2 Hz, 1H), 4.98-5.27 (m, 4H),4.38-4.52 (m, 3H), 3.58-3.86 (m, 2H), 2.68-2.90 (m, 2H), 1.84 (s, 3H),1.52 (s, 3H), 1.37 (s, 3H) [characteristic minor rotamer resonances δ9.36 (s), 8.21 (d, J=10.5 Hz), 7.82 (5, J=5.8 Hz), 4.89 (s), 4.78 (AB q,J_(AB)=9.8 Hz, Av=27.1 Hz), 4.17-4.24 (m), 2.93-3.01 (m), 1.87 (s), 1.41(s)]; ¹³C NMR (75 MHz, DMSO-d₆) displayed a ˜10:1 mixture of rotamers,major rotamer resonances δ 170.4, 169.5, 168.2, 155.7, 139.6, 139.4,135.5, 135.4, 129.9, 128.2, 126.2, 126.1, 121.9, 117.8, 115.6, 72.4,72.1, 53.1, 51.4, 48.2, 41.3, 34.2, 30.5, 25.0, 12.6 [characteristicminor rotamer resonances δ 171.4, 169.7, 168.6, 139.0, 129.5, 128.4,70.6, 54.2, 49.1, 41.5, 31.4, 24.8]; MS (CI) m/z 512.2224 (512.2219calcd for C₂₇H₃₄N₃O₅S, M+H⁺), elemental analysis calcd for C₂₇H₃₃N₃O₅S:C, 63.38; H, 6.50; N, 8.22; found: C, 63.19; H, 6.52; N, 8.10.

EXAMPLE F7 Preparation of (R)-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide; hydrochloride

A solution of (R)-5,5-Dimethyl-thiazolidine-3,4-dicarboxylic acid3-tert-butyl ester (105 kg, 402 mol) and ethyl acetate (690 L) wastreated with diphenylchlorophosphate (113 kg, 422 mol) and was thencooled to 0° C. NEt₃ (85.5 kg, 844 mol) was added while maintaining thetemperature at 5° C., and the mixture was then held at this temperaturefor 2 h. The mixture was cooled to 0° C., and allylamine (24.1 kg, 422mol) was then added while maintaining the temperature at 5° C. Themixture was warmed to 20° C. and was then quenched with 10 wt. % aqueousHCl (310 L). After separation of the layers, the organic fraction waswashed with 8.6 wt. % aqueous Na₂CO₃ (710 L). After separation of thelayers, the aqueous fraction was extracted with ethyl acetate (315 L).The combined ethyl acetate extracts containing AG-074278 were dried byazeotropic distillation at one atmosphere, while maintaining a minimumpot volume of approximately 315 L. The resulting suspension of(R)-4-Allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acidtert-butyl ester was cooled to 5° C. A 13 wt. % solution of anhydrousHCl (36.8 kg, 1008 mol) in ethyl acetate (263 L) was cooled to 5° C. andwas then added to the(R)-4-Allylcarbamoyl-5,5-dimethyl-thiazolidine-3-carboxylic acidtert-butyl ester suspension while maintaining the temperature at 15° C.The resulting suspension was held at 20° C. for 19 h, and was thencooled and held at 5° C. for 2 h. The suspension was then filtered,using cold ethyl acetate for rinsing. The wet cake was dried undervacuum at 45° C. to give 90.5 kg (95.2%) of(R)-5,5-Dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochlorideas a white solid: ¹H NMR (300 MHz, DMSO-d₆) δ 8.94 (app t, J=5.5 Hz,1H), 5.82 (ddt, J=10.4, 17.2, 5.2 Hz, 1H), 5.19-5.25 (m, 1H), 5.10-5.14(m, 1H), 4.38 (AB q, J_(AB)=9.8 Hz, Δν=14.5 Hz, 2H), 4.08 (s, 1H),3.72-3.91 (m, 2H), 1.58 (s, 3H), 1.32 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆)δ 161.7, 132.2, 114.0, 67.9, 51.4, 43.5, 39.3, 25.3, 24.3; MS (CI) m/z201.1070 (201.1062 calcd for C₉H₁₇N₂OS, M+H⁺); elemental analysis calcdfor C₉H₁₇ClN₂OS: C, 45.65; H, 7.24; N, 11.83; Cl, 14.97; found: C,45.41; H, 7.33; N, 11.69; Cl, 15.22.

EXAMPLE F8 Preparation of(2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyricacid

A mixture of (2S,3S)-3-Amino-2-hydroxy-4-phenyl-butyric acid (110 kg,563 mol), NaCl (195 kg), and THF (413 L) was charged with NEt₃ (120 kg,1183 mol) and H₂O (414 L) at ambient temperature. The resulting mixturewas cooled to 0° C. Acetic acid 3-chlorocarbonyl-2-methyl-phenyl ester(120 kg, 563 mol) was added to a separate reactor and was then dissolvedin THF (185 L). The resulting solution of acetic acid3-chlorocarbonyl-2-methyl-phenyl ester was cooled to 10° C., and wasthen added to the (2S,3S)-3-amino-2-hydroxy-4-phenyl-butyric acidmixture while maintaining the temperature <10° C. during addition. Theresulting biphasic mixture was agitated at 5° C. for 1 h, and was thenadjusted to pH 2.5-3.0 with concentrated HCl (62 kg). The mixture wasthen warmed to 25° C., and the layers were separated. The resulting THFfraction, containing(2S,3S)-3-(3-acetoxy-2-methyl-benzoylamino)-2-hydroxy-4-phenyl-butyricacid, was partially concentrated by distillation at one atmosphere. THFwas then replaced with ethyl acetate by distillation at one atmosphere,while maintaining a minimum pot volume of 1500 L. The resulting solutionwas cooled to 25° C., and was then charged with acetic anhydride (74.8kg, 733 mol) and methanesulfonic acid (10.8 kg, 112 mol). The mixturewas heated at 70° C. for approximately 3 h. The mixture was cooled to25° C., and was then quenched with H₂O (1320 L) while maintaining thetemperature at 20° C. After removal of the aqueous layer, the organicfraction was charged with ethyl acetate (658 L) and H₂O (563 L). Afteragitation, the aqueous phase was removed. The organic fraction waswashed twice with 13 wt. % aqueous NaCl (2×650 L). The organic fractionwas partially concentrated and dried by vacuum distillation (70-140 mmHg) to a volume of approximately 1500 L. The resulting solution washeated to 40° C., and was then charged with n-heptane (1042 L) whilemaintaining the temperature at 40° C. The solution was seeded with(2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyricacid (0.1 kg), and additional n-heptane (437 L) was then added slowly.The crystallizing mixture was maintained at 40° C. for 1 h. Additionaln-heptane (175 L) was added while maintaining the temperature at 40° C.The crystalline suspension was cooled and held at 25° C. for 1 h, thenat 0° C. for 2 h. The suspension was filtered, using n-heptane forrinsing. The wet cake was dried under vacuum at 55° C. to give 174 kg(74.5%) of(2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyricacid as a white solid: m.p.=152-154° C.; ¹H NMR (300 MHz, CDCl₃) δ7.21-7.35 (m, 5H), 7.13 (app t, J=7.9 Hz, 1H), 7.01 (app d, J=8.1 Hz,1H), 6.94 (app d, J=7.2 Hz, 1H), 5.99 (d, J=9.0 Hz, 1H), 5.33 (d, J=4.1Hz, 1H), 4.96-5.07 (m, 1H), 3.07 (dd, J=10 5.5, 14.6 Hz, 1H), 2.90 (dd,J=10.0, 14.5 Hz, 1H), 2.30 (s, 3H), 2.18 (s, 3H), 1.96 (s, 3H); ¹³C NMR(125 MHz, CDCl₃) δ 170.4, 170.2, 169.6, 169.5, 149.5, 137.81, 136.5,129.2, 128.6, 128.4, 127.0, 126.6, 124.5, 123.7, 73.1, 50.9, 35.9, 20.6,20.5, 12.4; elemental analysis calcd for C₂₂H₂₃NO₇: C, 63.92; H, 5.61;N, 3.39; found: C, 64.22; H, 5.68; N, 3.33; MS (CI) m/z 414.1572(414.1553 calcd for C₂₂H₂₄NO₇, M+H⁺).

EXAMPLE F9 Preparation of(4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide

A solution of(2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyricacid (140 kg, 339 mol), CH₃CN (560 L), and pyridine (64.3 kg, 813 mol)was cooled to 15° C. SOCl₂ (44.3 kg, 373 mol) was charged whilemaintaining the temperature at 15° C. The mixture was held at 15° C. for1 h. A separate reactor was charged with(R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide hydrochloride(96.6 kg, 408 mol), CH₃CN (254 L), and pyridine (29.5 kg, 373 mol), andwas then cooled to 15° C. The(2S,3S)-2-acetoxy-3-(3-acetoxy-2-methyl-benzoylamino)-4-phenyl-butyricacid chloride solution was added to the(R)-5,5-dimethyl-thiazolidine-4-carboxylic acid allylamide solution,while maintaining the temperature at 15° C. The mixture was held at 15°C. for 6 h. A separate reactor was charged with KOH (167 kg, 2709 mol)and methanol (280 L) using a 0° C. cooling jacket. The resultingKOH/methanol solution was cooled to 5° C. The crude acetic acid3-{(1S,2S)-2-acetoxy-3-[(R)-4-allylcarbamoyl-5,5-dimethyl-thiazolidin-3-yl]-1-benzyl-3-oxo-propylcarbamoyl}-2-methyl-phenylester mixture was added to the KOH/methanol solution while maintainingthe temperature at 10° C. After addition was complete, the mixture washeld at 25° C. for 3 h. The mixture was charged with H₂O (840 L) andethyl acetate (840 L), and was then followed by acidification to pH5-6.5 with concentrated HCl (85 kg) while maintaining the temperature at20° C. The resulting layers were separated. The organic fraction wassequentially washed with 6.8 wt. % aqueous NaHCO₃ (770 L), an aqueousHCl/NaCl solution (H₂O: 875 L; conc. HCl: 207 kg; NaCl: 56 kg), 8.5 wt.% aqueous NaHCO₃ (322 L), and then with 3.8 wt. % aqueous NaCl (728 L).The resulting organic fraction was partially concentrated bydistillation at one atmosphere. The solvent was exchanged with ethylacetate by continuing distillation and maintaining the pot temperatureat ≧70° C. Ethyl acetate was added such that the pot volume remained atapproximately 840 L. The solution was then cooled to 20° C. and held atthis temperature until crystallization was observed. n-Heptane (280 L)was added and the suspension was agitated at 15° C. for 4 h. Thecrystals were, using cold 2.4:1 (v/v) ethyl acetate/n-heptane forrinsing. The wet cake was dried under vacuum at 45° C. to provide crude(R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide. Decolorization and recrystallization was conducted asfollows: A mixture of crude(R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide, ADP carbon (21 kg), Supercel (3 kg), and ethyl acetate(780 L) was heated to 70° C. CH₃OH (40 L) was added to the mixture. Themixture was filtered, and the resulting clear filtrate was heated toreflux at one atmosphere to begin distillation. CH₃OH was displaced asfollows: ethyl acetate (388 L) was charged while maintaining the potvolume at approximately 840 L and at 70° C. The solution was slowlycharged with n-heptane (316 L), while maintaining a temperature of 70°C. The mixture was then cooled to 20° C. and was held at thistemperature for 4 h. The crystals were filtered, using cold 2.1:1 (v/v)ethyl acetate/n-heptane for rinsing. The wet cake was dried under vacuumat 45° C. to give 103 kg (59.6%) of(4R)-3-[(2S,3S)-2-hydroxy-3-(3-hydroxy-2-methyl-benzoylamino)-4-phenyl-butyryl]-5,5-dimethyl-thiazolidine-4-carboxylicacid allylamide as a white crystalline solid: mp=173-175° C., ¹H NMR(300 MHz, DMSO-d₆) displayed a ˜10:1 mixture of rotamers, major rotamerresonances δ 9.35 (s, 1H), 8.04-8.15 (m, 2H), 7.13-7.38 (m, 5H), 6.96(t, J=7.7 Hz, 1H), 6.79 (d, J=7.2 Hz, 1H), 6.55 (d, J=7.5 Hz, 1H),5.71-5.87 (m, 1H), 5.45 (br d, J=6.2 Hz, 1H), 4.98-5.27 (m, 4H),4.38-4.52 (m, 3H), 3.58-3.86 (m, 2H), 2.68-2.90 (m, 2H), 1.84 (s, 3H),1.52 (s, 3H), 1.37 (s, 3H) [characteristic minor rotamer resonances δ9.36 (s), 8.21 (d, J=10.5 Hz), 7.82 (5, J=5.8 Hz), 4.89 (s), 4.78 (AB q,J_(AB)=9.8 Hz, Av=27.1 Hz), 4.17-4.24 (m), 2.93-3.01 (m), 1.87 (s), 1.41(s)]; ¹³C NMR (75 MHz, DMSO-d₆) displayed a ˜10:1 mixture of rotamers,major rotamer resonances δ 170.4, 169.5, 168.2, 155.7, 139.6, 139.4,135.5, 135.4, 129.9, 128.2, 126.2, 126.1, 121.9, 117.8, 115.6, 72.4,72.1, 53.1, 51.4, 48.2, 41.3, 34.2, 30.5, 25.0, 12.6 [characteristicminor rotamer resonances δ 171.4, 169.7, 168.6, 139.0, 129.5, 128.4,70.6, 54.2, 49.1, 41.5, 31.4, 24.8]; MS (CI) m/z 512.2224 (512.2219calcd for C₂₇H₃₄N₃O₅S, M+H⁺), elemental analysis calcd for C₂₇H₃₃N₃O₅S:C, 63.38; H, 6.50; N, 8.22; found: C, 63.19; H, 6.52; N, 8.10.

Biological Evaluation

Cells and Virus

T-cell lines, CEM-SS, and MT-2, and viruses HIV-1 RF and HIV-1 NL4-3(pNL4-3) were obtained from the National Institutes of Health (AIDSResearch and Reference Reagent Program, Bethesda, MD). HIV-1NL4-3(I84V/L90M) was derived from a clinical isolate that exhibited theprotease inhibitor-resistance associated substitutions I84V and L90M, bycloning of an reverse transcriptase-polymerase chain reaction amplifiedfragment into the unique Age I and Spe I restriction sites of pNL4-3.

Cytopathic Effect (CPE) Inhibition Assays

The ability of compounds to protect cells against HIV infection wasmeasured by the MTT dye reduction method, essentially as described (SeePauwels, R. Balzarini, J. Baba, M. Snoeck, R. Schols, D. Herdewijn, P.Desmyter, J. and De Clercq, E. 1988, “Rapid and automatedtetrazolium-based calorimetric assay for the detection of anti-HIVcompounds,”. J Virol. Methods., 20: 309-321 and Weislow, O. S. Kiser, R.Fine, D. L. Bader, J. Shoemaker, R. H. and Boyd, M. R. 1989. “Newsoluble-formazan assay for HIV-1 cytopathic effects: application tohigh-flux screening of synthetic and natural products for AIDS-antiviralactivity”. J. Natl. Cancer Inst. 81:577-586). Subject cells wereinfected with test virus at an moi of 0.025 to 0.819 or mock infectedwith medium only and added at 2×10⁴ cells per well into 96 well platescontaining half-log dilutions of test compounds. Six days later, 50 μlof XTT (1 mg/ml XTT tetrazolium, 0.02 nm phenazine methosulfate) wasadded to the wells and the plate was reincubated for four hours.Viability, as determined by the amount of XTT formazan produced, wasquantified spectrophotometrically by absorbance at 450 nm. Data from CPEassays were expressed as the percent of formazan produced incompound-treated cells compared to formazan produced in wells ofuninfected, compound-free cells. The fifty percent effectiveconcentration (EC₅₀) was calculated as the concentration of compoundthat effected an increase in the percentage of formazan production ininfected, compound-treated cells to 50% of that produced by uninfected,compound-free cells. The 50% cytotoxicity concentration (CC₅₀) wascalculated as the concentration of compound that decreased thepercentage of formazan produced in uninfected, compound-treated cells to50% of that produced in uninfected, compound-free cells. The therapeuticindex was calculated by dividing the cytotoxicity (CC₅₀) by theantiviral activity (EC₅₀).

Susceptibility Assays

Compounds were tested in phenotypic susceptibility assays at Virologic,Inc., (See Petropoulos C. J., Parkin N. T., Limoli K. L., Lie Y. S.,Wrin T., Huang W., Tian H., Smith D., Winslow G. A., Capon D J, WhitcombJ M. 2000, “A novel phenotypic drug susceptibility assay for humanimmunodeficiency virus type 1,” Antimicrob Agents Chemother44(4):920-928) or using the assay described here. MT-2 cells wereinfected with either HIV-1 NL4-3 or HIV-1 NL4-3(I84V/L90M) and incubatedin the presence of serial 0.5 log dilutions of test compounds. Threedays later, culture supernatants were collected and virus production, asdetermined by p24 ELISA, was assayed. Percent inhibition was calculatedas p24 concentration in compound-treated samples as compared toinfected, compound-free controls. Inhibition of viral replication isdetermined by measuring reduction in HIV p24 present in the culturesupernatant, using a Beckman-Coulter p24 HIV-1 Ag EIA kit and followingthe supplied protocol. Absorbance is read on a MRX microplate reader(Dynex Technologies). The EC₅₀ was calculated as the concentration ofcompound that effected a decrease in the p24 production by infected,compound-treated cells to 50% of that produced by infected,compound-free cells.

HIV-1 Protease RET Assay

Ki's for the inhibitors of HIV-1 protease were determined using aresonance energy transfer (RET) assay. A mutant form of this enzyme(Q7S) is used for this assay because it is more stable againstauto-proteolysis than the wild-type protein. This enzyme is firstpartially purified as inclusion bodies from cell lysate. It is thensolublized in 8M urea and passed through a Q-Sepharose column(Pharmacia) for further purification. To refold this protein, samplescontaining Q7S is dialyzed into 50 mM sodium phosphate pH 7.0, 50 mMNaCl, 10 mM DTT, and 10% glycerol.

The commercially available peptide substrate (Molecular Probes Cat. #H-2930) RE(EDANS)SQNYPIVQK(DABCYL)R is used to assess activity and Ki's.This peptide is cleaved quantitatively by HIV-1 Pr at the Tyr-Pro bond.The EDANS fluorophore absorbs at 340 nm and emits at 490 nm. Thereaction is carried out in a 96 well plate in a total volume of 100 μLand is run for 12 minutes at 37C under steady-state conditions with 5 μMsubstrate and 2 nm active dimer enzyme concentration. The literaturevalue Km for this substrate and enzyme is 103+/−8 μM (See Matayoshi, etal., “Novel Fluorogenic Substrates for Assaying Retroviral Proteases byResonance Energy Transfer,” Science 247, 954 (1990)). The buffer forthis reaction is 0.1M sodium acetate pH 4.8, 1M NaCl, 1 mM EDTA, 5 mMdithiothreitol, 10% dimethyl sulfoxide and 1 mg/ml bovine serum albumin.Inhibition curves are fit using the Morrison tight binding equation.Example No. Ave. K_(i) (nM) Ave CPE EC₅₀ (mM) EC₅₀ or IC₅₀ (mM) A3 1.70.37 A4 4.1 0.591 A5 2 0.433 A6 0.22 0.036 A7 0.49 0.104 0.832 A8 0.230.036 A9 4 0.565 A10 51 >1 A11 19 0.93 A12 1.7 1.09 A13 44.1 >1 A14 0.440.052 0.071* A15 10.9 0.13 A16 0.63 0.134 A17 <0.1 0.045 0.102* A18 0.380.193 A19 10 0.442 A20 0.13 0.037 0.147* A21 1.9 0.717 A22 0.32 0.0610.226* A23 0.65 0.072 A24 0.18 0.104 0.831 A25 5.8 0.248 A26 0.38 0.1190.321* A27 0.62 0.072 A28 <0.1 0.041 A29 <0.1 0.117 A30 1.1 0.507 0.829*A31 <0.1 0.041 A32 <0.1 0.045 0.486 A33 <0.1 0.577 A34 <0.1 0.036 A35<0.1 0.017 0.063 A36 0.59 0.519 A37 0.13 0.161 A38 0.17 0.078 0.401 A390.27 0.367 A40 1.2 0.275 A41 1.6 0.527 A42 0.23 0.126 0.307 A43 0.350.561 A44 0.14 0.022 0.472 A45 0.51 0.165 A46 0.31 0.091 0.79 A47 2.31.813 A48 0.19 0.417 A49 1.2 0.13 A50 0.26 0.224 A51 1.3 0.667 A52 37 B12.5 0.905 B2 0.78 0.369 B3 4 0.409 B8 0.31 0.095 0.405* B4 1.7 0.551 B51.6 0.508 B6 1.6 0.589 B7 1.9 0.68 B8 1.5 0.552 B10 <0.1 1.1 B11 1.21.175 1.716* B12 0.45 1.398 B13 19%@64 nM B14 3.7 3.054 B15 2 1.086 B16<0.1 0.298 1.754 B17 0.42 0.534 1.579 B18 0.29 0.457 B19 <0.1 0.1241.369 B20 2.1 0.427 B21 4.6 0.598 B22 1.8 1.613 B23 0.42 1.42 B24 5.52.316 B25 2.7 1.794 B26 2.9 1.712 B27 3.5 B28 153 B29 0.12 1.256 B30 1.11.227 B31 1.5 1.316 B32 4.9 B33 1.2 1.286 B34 B35 B36 <0.1 0.615 B370.11 0.736 B38 B39 0.16 B40 2.8 1.396 B41 0.15 B42 0.73 B43 0.2 B44 0.760.629 B45 19.7 B46 12.5 B47 6.9 B48 12 >3.2 B49 17.2 C1 0.38 0.627 0.427C3 1.3 0.5 C4 4.2 C4 69 C5 3.2 C6 <0.1 0.164 1.475 C7 7.9 C8 0.26 0.447C9 0.34 0.233 C10 36 C11 1.1 1.562 D1 <0.01 0.052 0.601 D3 0.5 0.1621.954 D4 0.7 0.016 1.954*IC₅₀ (mM) Data was determined at Virologic Inc against the 46I, 84V,90M virus

The following compounds have been prepared according to the proceduresdescribed herein and have demonstrated the noted activity: MOLSTRUCTUREK_(i) EC₅₀

209 10

1700 10

0.1 0.053

62

0.75

0.1 0.072

1.5 0.076

0.2 0.113

0.73 0.141

0.36 0.144

0.24 0.158

0.26 0.207

0.17 0.289

0.11 0.334

0.2 0.585

9.6 0.723

4.7 1.064

1.1 1.114

2.5 1.221

7.4

2.6 1.3095

2.6 1.3095

3.4

3.7 1.332

72

2.3 1.378

11.1 1.401

2.6 1.416

2.1 1.488

14 1.512

18.5

19.5 3

12.1

10.5 3.2

17.3 3.303

16.8 3.745

13.1

0.1

28 4.132

0.1

24.6 4.951

55.8 10

214 10

The following compounds have been prepared according to the proceduresdescribed herein and have demonstrated the noted activity:

While the invention has been described in terms of preferred embodimentsand specific examples, those skilled in the art will recognize thatvarious changes and modifications can be made through routineexperimentation without departing from the spirit and scope of theinvention. Thus, the invention should be understood as not being limitedby the foregoing detailed description, but as being defined by theappended claims and their equivalents.

1. A process for preparing a compound of formula (I-A), or a prodrug,pharmaceutically active metabolite, or pharmaceutically active salt orsolvate thereof,

wherein: R¹ is a 5- or 6-membered mono-cyclic carbocyclic orheterocyclic group, wherein said carbocyclic or heterocyclic group issaturated, partially unsaturated or fully unsaturated and is optionallysubstituted by at least one substituent chosen from C₁₋₆ alkyl,hydroxyl, C₁₋₆ alkylcarbonyloxy, C₆₋₁₀ arylcarbonyloxy, andheteroarylcarbonyloxy; R² is C₂₋₆ alkenyl or C₁₋₆ alkyl optionallysubstituted with at least one halogen; R^(2′) is H or C₁₋₄ alkyl; Z isS, O, SO, SO₂, CH₂ or CFH; R³ is H or C₁-C₄ alkyl; and R⁴, R⁵, R⁶ and R⁷are independently chosen from H and C₁-C₆ alkyl; prepared by: reacting acompound of formula (II), wherein Y¹ is hydroxyl or a leaving group,with a compound of formula (III), or a salt or solvate thereof,


2. A process according to claim 1, wherein in the compound of formula(II), Y¹ is hydroxyl.
 3. A process according to claim 1, wherein in thecompound of formula (I-A): R¹ is phenyl optionally substituted by atleast one substituent independently chosen from C₁₋₆ alkyl, hydroxyl,C₁₋₆ alkylcarbonyloxy, C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy;and R⁴, R⁵, R⁶ and R⁷ are independently chosen from H and methyl.
 4. Aprocess according to claim 3, wherein in the compound of formula (I-A):R^(2′) is H; and Z is S, O, SO, or SO₂.
 5. A process according to claim4, wherein in the compound of formula (I-A) R² is C₂₋₆ alkenyl.
 6. Aprocess according to claim 5, wherein in the compound of formula (I-A):Z is S or O; and R³ is H.
 7. A process according to claim 6, wherein inthe compound of formula (I-A): Z is S; R⁴ and R⁵ are H; and R⁶ and R⁷are methyl.
 8. A process according to claim 7, wherein in the compoundof formula (I-A), R¹ is phenyl substituted by at least one substituentindependently chosen from C₁₋₆ alkyl, hydroxyl, C₁₋₆ alkylcarbonyloxy,C₆₋₁₀ arylcarbonyloxy, and heteroarylcarbonyloxy.
 9. A process accordingto claim 8, wherein in the compound of formula (I-A): R¹ is phenylsubstituted by C₁₋₆ alkyl and hydroxyl; and R² is allyl.
 10. A processaccording to claim 9, wherein in the compound of formula (I-A), R¹ isphenyl substituted by methyl and hydroxyl.
 11. A process according toclaim 10, wherein the compound of formula (I-A) is:


12. A process according to claim 8, wherein in the compound of formula(I-A), R¹ is phenyl substituted by at least one substituentindependently chosen from C₁₋₆ alkyl and C₁₋₆ alkylcarbonyloxy.
 13. Aprocess according to claim 12, wherein in the compound of formula (I-A):R¹ is phenyl substituted by methyl and methylcarbonyloxy; and R² isallyl.
 14. A process according to claim 13, wherein the compound offormula (I-A) is:


15. A process for preparing a compound of formula (I-B),

comprising: reacting a compound of formula (II-A) with a compound offormula (III-A), or a salt or solvate thereof,


16. A process for preparing a compound of formula (I-C),

comprising: (i) reacting a compound of formula (II-A) with a compound offormula (III-A), or a salt or solvate thereof,

 to afford a compound of formula (I-B); and (ii) deprotecting thecompound of formula (I-B).
 17. A process for preparing a compound offormula (I-C),

comprising: reacting a compound of formula (II-B) with a compound offormula (III-A), or a salt or solvate thereof,